bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12080: A Novel Adipokine Adipolin Prevents Pathological Vascular Remodeling Following Arterial Injury
Authors: Ogawa Hayato , Ohashi Koji , Shibata Rei , Ito Masanori , Otaka Naoya , Kawanishi Hiroshi , Murohara Toyoaki , Ouchi Noriyuki
Published: April 2024

Introduction:
Obesity is causally linked with the development of pathological remodeling of vascular wall. Previously we have demonstrated that adipolin, also known as C1q/TNF-related protein 12, is an adipokine that is down-regulated in obese rodents. Here, we investigated whether adipolin affects vascular response to injury using loss-of-function genetic manipulations.

Methods and Results:
No significant differences were observed in body weight, organ weights, blood pressure and blood glucose levels between adipolin-knockout (APL-KO) and wild type (WT) mice under basal conditions. APL-KO and WT mice were subjected to wire-induced injury of the left femoral artery. APL-KO mice exhibited an enhanced neointimal thickening after artery injury compared with WT mice. APL-KO mice also displayed an impaired re-endothelialization following vascular injury compared with WT mice. Treatment of human umbilical vein endothelial cells with recombinant adipolin protein promoted proliferation and reduced serum starvation-induced apoptosis. Adipolin treatment stimulated the phosphorylation of Akt and eNOS in endothelial cells. Pharmacological inhibition of PI3 kinase by treatment with LY294002 reversed the stimulatory effects of adipolin on endothelial cell growth and eNOS phosphorylation. Furthermore, APL-KO mice showed increased expression of pro-inflammatory cytokines including interleukin 6 and interleukin 1β in the injured artery as compared with WT mice. Consistently, treatment of mouse peritoneal macrophages with adipolin protein suppressed lipopolysaccharide-stimulated expression of pro-inflammatory mediators.

Conclusions:
Our data indicate that adipolin prevents pathological remodeling of vascular walls following injury by modulating endothelial cell function and macrophage inflammatory response.
Abstract 12087: Prevalence and Prognostic Implications of CMR Detected Myocardial Fibrosis in Patients With Mitral Valve Prolapse
Authors: Kitkungvan Danai , Nabi Faisal , Kim Raymond J , Bonow Robert , Xu Jiaqiong , Little Stephen H , Quinones Miguel , Lawrie Gerald , Zoghbi William A , Shah Dipan J
Published: April 2024

Background:
Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation (MR). Arrhythmia and sudden cardiac death (SCD) have been associated with MVP; however, the mechanism is unclear. Prior studies suggested left ventricular (LV) fibrosis as an arrhythmic substrate.

Hypothesis:
MVP patients have an increased prevalence of LV fibrosis which associated with adverse outcome.

Methods:
Patients referred for CMR to assess mitral valve disease were enrolled. Confounding causes of LV fibrosis (CAD, LVEF < 50% etc.) and secondary MR were excluded. Primary MR patients were classified into MVP (>2 mm leaflet displacement) and a non-MVP group. Cine, phase contrast CMR were performed to assess cardiac morphology/function and MR severity. Late gadolinium enhancement (LGE) CMR was performed to identify LV fibrosis. Patients were followed for 1) arrhythmic events comprised of SCD/aborted SCD, or sustained/inducible ventricular arrhythmia requiring ICD and 2) composite outcome that included arrhythmic events or cardiovascular death.

Results:
356 primary MR patients (177 MVP, and 179 non-MVP) were enrolled. Baseline characteristics were relatively similar except MVP patients had more severe MR (MR fraction 42.1±14.3% vs. 32.8±12.2%, p<0.03). LGE representing LV fibrosis was more prevalent in MVP group (36.7% vs. 6.7%, p<0.001) and for each MR severity (figure 1A). On multivariate analysis, although lower LVEF, and increasing MR severity were associated with increased LV fibrosis, presence of MVP had the strongest association (OR 6.82, p < 0.001). During the follow up period (median 673 days), MVP patients with LV fibrosis had the highest annualized event rate for arrhythmic events and composite outcome (figure1B).

Conclusion:
LV fibrosis is more prevalent in MVP than non-MVP patients with primary MR suggesting a unique pathophysiology in MVP. Presence of LV fibrosis in MVP may represent a risk marker of arrhythmic events and adverse clinical outcome.
Abstract 12149: Severe Obesity, but not Overweight, is Associated With Short- and Long-term Decreased Mortality in Patients With Type 2 Diabetes Hospitalized for Acute Decompensated Heart Failure: Findings From the Gulf-care
Authors: Abi Khalil Charbel , Suleiman Kadhim , Singh Rajvir , Asaad Nidal , Jayyousi Amin , Al Suwaidi Jassim ,   On behalf of the GULF-CARE Investigators
Published: April 2024

Introduction:
A U-shaped relationship has been reported between BMI and cardiovascular events among patients with acute decompensated heart failure (ADHF).

Hypothesis:
We hypothesized that an obesity paradox governs the relationship between BMI and mortality in patients with type 2 diabetes (T2D) and ADHF.

Methods:
The Gulf-CARE (Gulf aCute heArt failuRe rEgistry) is a prospective multicenter study of 5005 consecutive patients hospitalized with acute heart failure in 7 Middle Eastern countries. We studied 3-month and 12-month mortality in patients with T2D hospitalized for ADHF according to 5 BMI categories: Underweight (<20 kg/m
2
), normal weight (referent group, 20-24.9 kg/m
2
), overweight
,
(25-29.9 kg/m
2
), obese (30-34.9 kg/m
2
) and severely obese (>=35 kg/m
2
).

Results:
Among the 5005 patients admitted in the GULF-CARE registry, 2492 (49.8%) had T2D. Underweight patients had a higher 3-month and 12-month mortality risk (OR 2.04, 95% CI [1.02-4.08], p= 0.04; OR 2.44, 95% CI [1.35-4.3], p=0.003; respectively), compared to normal weight. Overweight and obese patients had a mortality risk similar to that of normal weight. However, severe obesity (BMI >=35 kg/m
2
) was associated with a lower 3-month and 6-month mortality risk (OR 0.53, 95% CI [0.34-0.83], p=0.005; OR 0.58, 95% CI [0.42-0.81]; p=0.01; respectively). After adjustment for several risk variables, including age, gender, hypertension, smoking, dyslipidemia, LVEF, heart rate, ADHF etiology, BP and medications at discharge, the primary outcome was still significantly increased in underweight patients at 3 months and 12 months, and decreased in severely obese patients for the same period.

Conclusions:
In this cohort of patients with ADHF, a U-shape relationship between BMI and mortality was not found in patients with T2D. Protection against long-term mortality increases in obese patients, reaching a significant peak in severely obese ones.

Figure 1:
12-month mortality risk. * p= 0.004; ** p= 0.008
Abstract 12150: Molecular Network Analysis Identifies NEDD9 as a Critical Node Regulating Vascular Fibrosis in Pulmonary Arterial Hypertension
Authors: Stephens Thomas E , Wang Rui-Sheng , Samokhin Andriy , Cao Minwei , Arons Elena , Vargas Sara O , Loscalzo Joseph , Leopold Jane A , Maron Bradley A
Published: April 2024

Vascular fibrosis in pulmonary arterial hypertension (PAH) is associated with increased morbidity. In PAH, elevated levels of aldosterone (ALDO) increase fibrillar collagen in pulmonary artery endothelial cells (PAECs). However, ALDO also promotes adaptive fibrosis in skin wound healing, suggesting that cell type-specific pathways regulated by ALDO distinguish fibrosis subtypes. To explore this concept further, published mRNA array data were used to model an interactome of fibrosis-related genes. Betweeness centrality analysis identified the Crk-associated protein NEDD9 as a critical ALDO-regulated node distinguishing vascular from dermal fibrosis (P=7.5x10
-7
vs. random network). To validate this observation, PAECs and dermal microvascular ECs were treated with ALDO (10
-7
mol/L) or vehicle control (V) for 24 hr and NEDD9 levels were analyzed by immunoblot. Compared to V-treated cells, ALDO increased NEDD9 expression in PAECs (46 ± 12 vs. 90 ± 7 a.u., P<0.05) but not dermal microvascular ECs (P=NS). To determine the relevance of NEDD9 to fibrosis in PAH, anti-NEDD9 immunohistochemistry was performed on explanted lung tissue from patients. Compared to controls, PAH patients had increased pulmonary arteriole NEDD9 (32 ± 2.8 vs. 69 ± 12 a.u., P<0.05), which correlated with collagen deposition levels assessed by Gomori trichrome stain (r=0.73, P<0.02) and was confirmed by confocal microscopy imaging demonstrating increased overlap between collagen III and NEDD9 expression in PAH pulmonary arterioles. We next analyzed the functional effect of NEDD9 on ALDO-induced collagen III in PAECs
in vitro
. Compared to V-treated cells, ALDO increased collagen III expression (117 ± 16 vs. 225 ± 34 a.u., P<0.01) and the number of Gomori stain positive PAECs (2.1 ± 0.8 vs. 8.1 ± 0.6 cells/h.p.f., P<0.01). By contrast, si-NEDD9 decreased collagen III and fibrosis in ALDO-treated cells by 81% (P<0.03) and 70.5% (P<0.01), respectively. Overall, we used a systems approach to demonstrate NEDD9 targeting by ALDO as a key mechanism defining pathogenic fibrosis. Identifying fibrillar collagen regulation by NEDD9 in PAECs may have novel therapeutic implications for patients with PAH and other diseases characterized by pulmonary vascular fibrosis.
Abstract 12201: Infants With 22q11.2 Deletion Syndrome Undergoing Repair of Tetralogy of Fallot, Interrupted Aortic Arch, and Truncus Arteriosus have Longer Hospitalizations and Increased Rates of Infection
Authors: Olive Mary K , Mery Carlos M , Wallace Amelia S , Hill Kevin D , Jacobs Jeffrey P , Austin Erle H , Pasquali Sara K , Jacobs Marshall L , Heinle Jeffrey S , Penny Daniel J
Published: April 2024

Introduction:
22q11.2 deletion syndrome (22q11del) is common in patients with certain types of congenital heart disease. The prevalence of 22q11del and its impact on clinical outcomes remains unclear as only small single center studies are available and have shown conflicting data.

Methods:
All infants with tetralogy of Fallot (TOF), truncus arteriosus (TA), interrupted aortic arch (IAA), or IAA+TA included in the STS Congenital Heart Surgery Database from 1/10 to 6/15 were included. Infants with single ventricle lesions, pulmonary atresia with MAPCAs, and trisomies were excluded. Perioperative mortality and STS-defined major morbidities were compared between patients with and without 22q11del. Analyses were performed using Wilcoxon rank sum or chi-square tests.

Results:
A total of 5,179 patients were included. 22q11del was present in 255 (6.3%) patients with TOF, 160 (28.8%) with TA, 206 (38.4%) with IAA, and 19 (28.8%) with IAA+TA undergoing repair. For all procedural cohorts, there was no significant difference in perioperative mortality between the two groups. Infants with 22q11del had a longer hospitalization and a higher incidence of postoperative infections (Table). Within the TOF cohort only, infants with 22q11del had a higher incidence of the STS-defined composite major morbidity measure (12.5% vs. 6.1%, p<0.01), largely driven by an increased incidence of unplanned re-interventions (9.9% vs. 4.3%, p<0.01) and phrenic nerve injuries (2.5% vs. 0.8%, p=0.01).

Conclusions:
22q11del is common in infants undergoing repair of TOF, TA, IAA, and IAA+TA. While operative mortality for the diagnostic groups was not impacted by 22q11del, patients with 22q11del did have longer hospitalizations and a higher incidence of infectious complications. Families should be counseled appropriately and further strategies should be developed to limit the morbidity in patients with 22q11del undergoing congenital heart surgery.
Abstract 12440: Impact of Changes in the Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care on Neurologically Intact Survival
Authors: Nagao Ken , Nonogi Hiroshi , Yonemoto Naohiro , Gaieski David F , Ito Noritoshi , Takayama Morimasa , Shirai Shinichi , Furuya Singo , Tani Sigemasa , Yagi Tsukasa , Tachibana Eizo , Kimura Takeshi , Saku Keijiro
Published: April 2024

Introduction:
The AHA and International Liaison Committee on Resuscitation (ILCOR) published the Guidelines 2000 for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC). Since 2000, the ILCOR has reported the International Consensus on CPR and ECC Science with Treatment Recommendations (CoSTR) in 5-year cycles. However, few nationwide studies have investigated the efficacy of changes in the CPR guidelines.

Methods:
A total of 1,136,283 adult patients who received CPR after out-of-hospital cardiac arrest (OHCA) between 2005 and 2014 were included from the All-Japan Utstein Registry, a prospective, nationwide, population-based registry. We divided the study patients into 3 groups according to each guideline era (the G2000 era was cases in 2005, the CoSTR2005 era from 2006 to 2010 and the CoSTR2010 era from 2011 to 2014). The primary endpoint was favorable 30-day neurological outcome after OHCA. Multiple logistic regression analysis for primary endpoint was performed to adjust for possible confounders due to imbalances in baseline characteristics.

Results:
Of the 1,136,283 patients, 100,509 (8.8%) were in the G2000 era, 549,147 (48.3%) in the CoSTR2005 era and 486,627 (42.8%) in the CoSTR2010 era. Baseline characteristics exhibited significant differences among the three groups, including age, sex, time interval from call receipt to paramedic arrival at patient’s side, arrest witnessed, bystander CPR, initial arrest rhythm, advanced CPR, cause of OHCA, etc. After adjustment for resuscitation, the CoSTR2005 and the CoSTR2010 (reference, the G2000) were independent predictor of favorable 30-day neurological outcome (the CoSTR2005: adjusted OR, 1.588; 95% CI: 1.488-1.696, and the CoSTR2010: adjusted OR, 2.100; 95% CI: 1.966-2.242, respectively) and the subgroups of patients with even unwitnessed OHCA (the CoSTR2005: adjusted OR, 1.210; 95% CI: 1.057-1.386, and the CoSTR2010: adjusted OR, 1.484; 95% CI: 1.296-1.700, respectively).

Conclusions:
In a nationwide study for all adult patients with OHCA, the CoSTR2005 had favorable neurological outcome 1.6 times as high as the G2000, and also the CoSTR2010 had it 2.2 times. The neurologically intact survival increased each time the CPR guidelines were changed.
Abstract 12475: Mechanisms of Akt1-mediated Hypothermia Protection After Cardiac Arrest: Metabolism, Inflammation and Contractile Function
Authors: Li Jing , Wang Huashan , Lee Chunpei , Chen Sy-Jou , Zhu Xiangdong , Qian Yuanyu , Bunney Ryan H , Beiser David G , Vanden Hoek Terry L
Published: April 2024

Introduction:
Induction of intra-arrest cooling (IC) improves cardiac, neurological and survival outcomes in preclinical models of cardiac arrest. Previous studies demonstrate that IC protection is mediated by Akt1 activation through initiating survival signaling.

Hypothesis:
We hypothesize that IC-induced Akt1 activation modulates protective calcium cycling proteins, metabolic, and inflammatory pathways.

Methods:
Adult female Akt1
+/-
underwent 8 min of KCl-induced asystolic arrest and were randomized to receive IC (30 ± 0.5°C) or normothermia (NT) before CPR (n = 10 per group). 72 h survival and mean blood pressure (MAP) were measured. Indicators of glucose utilization, inflammatory responses and contractile function in heart and brain of Akt1
+/+
and Akt1
+/-
mice were assessed (n=5 per group).

Results:
No difference on survival was seen for IC and NT treated Akt1
+/-
mice. IC induced transient improvement in MAP at 30 min following resuscitation (53.6 ± 2.2 vs 71.2 ± 2.6 mmHg p<0.05) and increased phospholamban phosphorylation in the heart of Akt1
+/+
mice which were not seen in Akt1
+/-
mice. Compared to IC-treated Akt1
+/+
, pyruvate dehydrogenase phosphorylation and sorbitol accumulation were significantly increased, and NAD and ATP contents were markedly reduced in the hearts and brains of Akt1
+/-
mice. IC significantly inhibited IκBα degradation and NF-κB nuclear translocation, and reduced concentrations of blood lactate and Pre-B cell Colony Enhancing Factor in Akt1
+/+
mice, but not Akt1
+/-
mice.

Conclusion:
Akt1 is a critical mediator for TH protection during early post resuscitation in heart and brain through regulating calcium regulatory proteins, enhancing glucose utilization and downregulating inflammatory responses.
Abstract 12795: Impact of Right Ventricular Outflow Tract Obstruction on Right Ventricular Remodeling and Exercise Capacity in Patients With Severe Pulmonary Regurgitation After Repair of Tetralogy of Fallot
Authors: Chen Qiuming , Li Shoujun , Yang Keming , Pan Xiangbin , Hua Zhongdong , Zhang Hao , Lu Minjie , Sun Xingguo , Ma Kai , Zhang Sen , Qi Lei
Published: April 2024

Introduction:
The long-term impact of right ventricular outflow tract obstruction (RVOTO) in patients with severe pulmonary regurgitation after repair of tetralogy of Fallot are controversial.

Hypothesis:
We hypothesize that patients with combined PR and RVOTO have better RV remolding and exercise capacity than patients with isolated PR.

Methods:
This is a retrospective cohort study of ninety-one consecutive patients with severe PR detected on echocardiography and evaluated with cardiac magnetic resonance and cardiopulmonary exercise test between 2012 and 2016. Twenty-three patients had combined PR and RVOTO (Doppler peak RVOT gradient ≥30 mmHg), while the other had isolated PR (n=68).

Results:
In spite of similar PR fraction between the two groups, patients with combined PR and RVOTO had significantly smaller RV end-diastolic volume (129.1 ± 32.7 vs 163.3 ± 53.9 ml/m
2
, p=0.020) and RV end-systolic volume (84.9 ± 26.5 vs 110.8 ± 48.2 ml/m
2
, P= 0.006) than patients with isolated PR. No significant difference was detected in RV ejection fraction and left ventricle volumes and function between the two groups. Multivariable linear regression analysis identified that transannular repair and peak pressure gradient of RVOT as independent predictors for RV volume. Patients with combined PR and RVOTO had higher (24.9 ± 5.2 vs 20.1 ± 6.3 ml/kg/min, P=0.07) peak oxygen uptake than patients with isolated PR. Peak RVOT gradient was the only independent predictor of exercise capacity in patients with combined PR and RVOTO.

Conclusions:
Patients with combined PR and RVOTO had less dilated RV and better exercise capacity than those with isolated PR. An acceptable residual RVOTO is more advantageous in the long-term outcome of repaired TOF.
Abstract 12806: Advanced Airway Management May Not be Effective Compared to Basic Airway Management After Pediatric Out-of-hospital Cardiac Arrest
Authors: Fukuda Tatsuma , Ohashi-Fukuda Naoko , Hayase Naoki , Wada Tomoki , Matsubara Takehiro , Doi Kent , Yahagi Naoki
Published: April 2024

Introduction:
Respiratory care for pediatric out-of-hospital cardiac arrest (OHCA) may play an important role due to the asphyxial nature of the majority of pediatric OHCA events.

Hypothesis:
We assessed the hypothesis that prehospital advanced airway management (endotracheal intubation or supraglottic airway device) is associated with an increased chance of favorable outcomes compared with basic airway management (bag-valve-mask ventilation) after pediatric OHCA.

Methods:
This was a nationwide, population-based, propensity score-matched study of pediatric OHCA in Japan from January 1, 2011, to December 31, 2012, based on data from the All-Japan Utstein Registry. We included pediatric patients aged < 18 years. Infants (≤ 1 year old) were excluded. The primary outcome was a favorable neurological state one month after OHCA defined as a Glasgow-Pittsburgh cerebral performance category (CPC) score of 1-2 (corresponding to a Pediatric CPC score of 1-3). The secondary outcomes included a neurologically favorable survival with a CPC score of 1 (corresponding to a Pediatric CPC score of 1), one-month survival, and prehospital return of spontaneous circulation (ROSC).

Results:
A total of 2,157 patients were included in the final cohort; 365 received advanced airway management and 1,792 received basic airway management. Among 2,157 patients, 213 (9.9%) survived with a favorable neurological status one month after OHCA. There were no significant differences in neurologically favorable survival between the advanced airway management group and the basic airway management group after adjusting for potential confounders: propensity score matching, OR 0.74 (95%CI 0.35-1.59), and multivariable logistic regression modeling, OR 0.55 (95% CI 0.24-1.14). Similar findings were observed for the secondary outcomes. In subgroup analyses (including the non-cardiac [mainly asphyxial] etiology group), there were no subgroups in which advanced airway management was associated with neurologically favorable survival.

Conclusions:
In conclusion, advanced airway management was not associated with an increased chance of neurologically favorable survival, one-month survival, or prehospital ROSC compared to basic airway management after pediatric OHCA.
Abstract 12809: Abnormal P-Wave Axis is Associated With an Increased Risk of Ischemic Stroke: The Atherosclerosis Risk In Communities (ARIC) Study
Authors: Maheshwari Ankit , Norby Faye L , Soliman Elsayed Z , O’Neal Wesley T , Alonso Alvaro , Chen Lin Y
Published: April 2024

Introduction:
Abnormal P-wave axis (aPWA) has been linked to incident atrial fibrillation (AF) and mortality; however, the relationship between aPWA and stroke has not been reported.

Hypothesis:
We hypothesized that aPWA is associated with ischemic stroke independent of AF and other stroke risk factors and tested our hypothesis in the Atherosclerosis Risk In Communities (ARIC) study, a community-based prospective cohort study.

Methods:
We included 15,102 participants (age, 54.2 ± 5.7 yrs, 55.2% women, 26.5% blacks) who attended the baseline exam (1987-89) and without prevalent stroke. We defined aPWA as any value outside 0-75 degrees using 12-lead ECGs obtained during the baseline exam. Incident ischemic stroke was identified by annual phone interviews, hospital discharge records, and death certificates. Each case was classified in accordance with criteria from the National Survey of Stroke by a computer algorithm and adjudicated by physician review. Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of aPWA with stroke.

Results:
During a mean follow-up of 20.2 years, there were 1027 incident ischemic stroke cases. aPWA was independently associated with a 1.37-fold (95% CI, 1.11-1.69) increased risk of ischemic stroke in the multivariable model. After further adjustment for AF, aPWA remained independently associated with a 1.30-fold (95% CI,1.05-1.61) increased risk of ischemic stroke.

Conclusions:
aPWA was independently associated with ischemic stroke. This finding suggests that abnormalities in atrial electrical activation are associated with ischemic stroke independent of AF.
Abstract 12823: Estimated Cardiorespiratory Fitness and Incident Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Bose Abhishek , O’Neal Wesley T , Bennett Aleena , Judd Suzanne E , Qureshi Waqas T , Sui Xuemei , Howard Virginia J , Howard George , Soliman Elsayed Z
Published: April 2024

Background:
Poor cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular disease (CVD). However, wide utilization of CRF in CVD risk assessment is limited due to its cost, and the need for exercise equipment and skilled personnel. Estimated CRF (e-CRF) based on readily available clinical and self-reported data is a promising alternative though its role as a predictor of incident atrial fibrillation (AF) remains unclear.

Methods:
This study included 10,126 participants (54.5% women, 35% African American, mean age 63.2 years) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of AF at the time of enrollment (2003-2007). Baseline e-CRF was determined using non-exercise algorithms (Table footnote). Incident AF cases were identified at a follow-up examination by electrocardiogram or self-reported medical history. Multivariable logistic regression was used to calculate the odds ratio (ORs) and 95% confidence intervals (CIs) for the association between baseline e-CRF and incident AF.

Results:
After a median follow-up of 9.4 years, 906 (8.9%) participants developed AF. In a multivariable model adjusted for demographics, baseline CVD risk factors, and potential confounders, each 1-unit increase in e-CRF was associated with a 5% lower risk of AF development (p=0.007). This association remained significant after further adjustment for incident coronary heart disease, heart failure, and stroke, and was stronger in women than men (interaction p-value =0.05). No significant interaction by age, sex, race, history of CVD, or physical limitations was observed.

Conclusion:
e-CRF using non-exercise algorithms is a useful predictor of incident AF, and the protective effect is more pronounced among women. e-CRF using non-exercise algorithms may serve as a useful alternative to CRF measured by costly and time consuming exercise testing.
Abstract 12827: Detection of Spontaneous Pulse Using Acceleration Signals Acquired From CPR Feedback Sensor in Porcine Model of Cardiac Arrest
Authors: Wei Liang , Yu Tao , Gao Peng , Quan Weilun , Li Yongqin
Published: April 2024

Background:
Reliable detection of return of spontaneous circulation (ROSC) without long interruptions of chest compressions is part of high-quality cardiopulmonary resuscitation (CPR) and routinely done by checking pulsation of carotid or femoral arteries. The purpose of the current study was to investigate whether acceleration signals acquired from a CPR feedback sensor can be used to distinguish perfusing rhythm from pulseless electrical activity (PEA) in a porcine model of cardiac arrest.

Methods:
The experimental data were collected from 50 male adult pigs with prolonged cardiac arrest and CPR. ECG, arterial blood pressure and acceleration signals were synchronously recorded at a sample rate of 300 Hz. The acceleration signal (ACC) was acquired from an accelerometer-based CPR sensor that was placed on the surface of the animal’s chest over the heart. During chest compression pauses 3-second segments of signals were extracted. ROSC was defined as systolic arterial pressure (SAP) >60 mmHg and pulse pressure (PP) >10 mmHg in the presence of an organized rhythm. ACC was pre-processed using a narrow band-pass filter with the center frequency from 0.5 to 7.5Hz. Cross-correlation function was calculated between ECG and filtered ACC to obtain the peak correlation coefficient (CCp). Area under the receiver operating characteristic curve (AUC) was used to evaluate the ability of CCp to detect ROSC.

Results:
A total of 216 segments were obtained with 63 in perfusing rhythm and 153 in PEA. The filtered ACC tracings (ACC’) in perfusing rhythm showed periodic oscillations synchronized with R waves, but no periodic oscillations were observed for PEA. Compared with PEA, heart rate (159.0±50.7 vs. 86.0±44.9 bpm,
p
<0.01), SAP (143.3±38.3 vs. 18.9±13.3 mmHg,
p
<0.01), pulse pressure (42.3±14.5 vs. 5.6±8.3 mmHg,
p
<0.01) and CCp (0.443±0.171 vs. 0.096±0.085,
p
<0.01) were significantly higher for perfusing rhythm. The AUC was 0.95 when CCp was used to differentiate ROSC from PEA. Using a cut-off threshold of 0.244, the sensitivity and specificity were 90.5% respectively.

Conclusions:
In this animal model, the acceleration signals acquired from a CPR feedback sensor can be used to distinguish perfusing rhythm from PEA.
Abstract 12882: Provider Rather Than Patient Misperceptions Appear to be the Most Common Barriers to Oral Anticoagulation Use for Stroke Prevention in Atrial Fibrillation
Authors: Pokorney Sean D , Granger Christopher B , Bloom Diane , Thomas Kevin L , Al-Khatib Sana M , Anderson John , Heflin Mitchell T , Granger Bradi B
Published: April 2024

Introduction:
Atrial fibrillation (AF) is associated with increased risk of stroke, yet 50% of patients at high risk are not treated with guideline recommended oral anticoagulants (OACs). This qualitative analysis explored the barriers to OAC use from both physician and patient perspectives.

Methods:
Patients (n=25) from academic and community care settings with AF and CHA
2
DS
2
-VASc score ≥ 2 were included with a maximum variation sampling strategy for patients on OAC (n=13) and not on OAC (n=12). Provider sampling (n=25) included community primary care providers (n=15), academic geriatricians (n=5), and cardiologists (n=5) caring for the patient cohort. Semi-structured qualitative interviews were conducted with both groups focusing on perceptions of stroke risk and OAC use. Provider interviews used 3 standard AF cases to ascertain how stroke and bleeding risks affected OAC recommendation. Interviews continued until saturation of themes was achieved. Content analysis identified and coded dominant themes.

Results:
A major theme was missing evidence of shared decision-making for OAC use. A majority of patients “took what was prescribed.” Nearly all physicians reported fall and bleeding risks as the primary reasons for not recommending OACs, but patients reported no communication with their physicians about falls or bleeding risk, other than in the setting of prior bleeding (Table). A second major theme was the knowledge gap in the lack of efficacy of aspirin for stroke prevention and the need for OAC in patients with infrequent or mildly symptomatic AF. Physicians (92%) understood that infrequent AF episodes required OAC, but in 33% of cases, patients with infrequent AF episodes were told that OACs were not warranted (Table).

Conclusions:
These findings suggest that provider rather than patient concerns prevent appropriate OAC. Opportunities exist, particularly among non-cardiology providers, to increase the appropriate OAC use for AF patients at risk of stroke.
Abstract 12932: Loss of Small Ubiquitin-Like Modifier 1 Protects the Heart From Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction in Mice
Authors: Zheng Liuying , Sheng Huaxin , Du Xinping , Zuo Guoxing , Wang Kuan , Paschen Wulf , Yang Wei
Published: April 2024

Introduction:
Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a post-translational modification, modulates activity of a large number of nuclear proteins, including transcriptional factors and chromatin-associated proteins, and plays a crucial role in heart development and pathogenesis of heart diseases. It was reported that levels of SUMO1 significantly decrease in human failing hearts, overexpression of SUMO1 improves cardiac function in a mouse model of heart failure. To clarify whether SUMO1 does indeed play a critical role in heart disease, we compared outcome after transverse aortic constriction (TAC) in wild- type (WT) and Sumo1 knockout (SUMO1-KO) mice.

Methods and Results:
SUMO1-KO and WT littermate mice were subjected to TAC. Echocardiography analysis of cardiac function was performed at 8 weeks after TAC. The effect of SUMO1 deletion on regulation of expression of hypertrophy-related genes was evaluated by qPCR, Western blot, and chromatin immunoprecipitation assay. Compared to WT mice, SUMO1-KO mice showed a significantly lower ratio of left ventricular (LV) weight to body weight (5.73±0.49 mg/g vs 6.76±1.11mg/g;
p
<0.05,n=8) and smaller transverse section area of cardiomyocyte (259±47 μm
2
vs 328±56 μm
2
,
p
<0.05,n=3). Moreover, in SUMO1-KO mice, LV diameters in end-diastole and end-systole were significantly shorter, while percentage of LV fractional shortening was higher (51.64±6.24% vs 40.63±15.46%;
p
<0.05,n=10). Furthermore, the TAC-induced increase in mRNA and protein levels of ANF, BNP, SKA, and β-MHC was significantly less in SUMO1-KO than in WT mice. Finally, we found that the enrichment of chromatin-bound SUMO2/3 on promoters of selected hypertrophy-related genes was higher in SUMO1-KO than in WT mice after TAC.

Conclusions:
Our results do not support a model whereby SUMO1 is critical for outcome after TAC. The data imply that increased chromatin-bound SUMO2/3 at the promoters of key hypertrophy-related genes suppressed their expression and thereby contributed to the beneficial effect of SUMO1 deletion. This suggests a novel, not yet recognized, aspect of redundancy of the SUMOylation system. Therefore, SUMO2/3 may be better suited than SUMO1 to counterbalance SUMO1 depletion in heart failure.
Abstract 12982: Abnormal P-Wave Axis is Associated With an Increased Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Maheshwari Ankit , Norby Faye L , O’Neal Wesley T , Soliman Elsayed Z , Alonso Alvaro , Chen Lin Y
Published: April 2024

Introduction:
P-wave indices, such as prolonged p-wave duration and abnormal p-wave terminal force in V1, have been associated with incident AF.

Hypothesis:
We hypothesized that abnormal p-wave axis (aPWA) is associated with AF independent of traditional cardiovascular risk factors and tested our hypothesis in the ARIC study, a community-based prospective cohort study.

Methods:
We included in 15,319 participants without prevalent AF (age, 54.2 ± 5.7 yrs, 55.2% women, 26.5% blacks) who attended the baseline exam (1987-89). We defined aPWA as any value outside 0-75 degrees using 12-lead ECGs obtained during the baseline exam. Incident AF was identified by hospital discharge records, death certificates, and ECGs obtained during the study examinations. We used Cox proportional hazard models to estimate the hazard ratios and 95% confidence intervals of aPWA for AF.

Results:
During a mean follow-up of 19.8 years (1987-2012), there were 2377 incident AF cases. aPWA was independently associated with a 1.41-fold (95% CI, 1.22-1.62) increased risk of AF in the multivariable model (Table).

Conclusions:
aPWA is independently associated with incident AF in the general population. Further research is warranted to evaluate the ability of this readily available ECG measure in improving risk prediction of AF.
Abstract 12984: Long-term Therapy With Elamipretide Normalizes Protein Levels of the Signal Transducer and Activator of Transcription 3 (STAT3) in Mitochondria of Left Ventricular Myocardium of Dogs With Chronic Heart Failure
Authors: Gupta Ramesh C , Singh-Gupta Vinita , Zhang Kefei , Xu Jiang , Sabbah Hani N
Published: April 2024

Introduction:
The signal transducer and activator of transcription 3 (STAT3) has recently been identified in mitochondria (MITO) of cardiomyocytes (mSTAT3). In STAT3-/- cells, the activities of MITO complexes I and II of the electron transport chain (ETC) were significantly reduced suggesting that mSTAT3 is required for optimal ETC function. In the heart, mSTAT3 activity is modulated by the heat shock protein H11 kinase (H11K) previously shown to be reduced in MITO of dogs with HF. We showed that long-term (3 months) therapy with elamipretide (ELA,

Bendavia
TM

), a novel MITO-targeting peptide, improves LV systolic function and to normalize MITO respiration, rate of ATP synthesis and H11K levels in MITO of LV cardiomyocytes of dogs with heart failure (HF).

Hypothesis:
This study tested the hypothesis that the level of mSTAT3 is reduced in LV myocardium of dogs with HF and that long-term therapy with ELA restores levels of mSTAT3.

Methods:
LV tissue was obtained from 14 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 6 normal dogs was used for comparison. Protein levels of mSTAT3 and porin; the latter a MITO protein unchanged in HF (internal control), were determined in isolated MITO fractions from LV tissue using by Western blotting coupled with chemiluminescence. Protein band intensities were quantified in densitometric units (du).

Results:
Protein levels of porin was similar in all 3 study groups (NL:0.24±0.01; Control: 0.22±0.01; ELA: 0.23±0.01 du). Levels of mSTAT3 were 0.82±0.05 du in NL, decreased to 0.29±0.03 du in Controls (p<0.05 vs. NL) and were partially restored by ELA (0.53±0.05, p<0.05 vs. Control). Levels of mSTAT3 normalized to porin were 3.6±0.3 du in NL, decreased to 1.3±0.1 in Controls (p<0.05 vs. NL) and were restored to near normal levels following treatment with ELA (2.3±0.2, p<0.05 vs. Control).

Conclusions:
mSTAT3 level is reduced in MITO of from LV myocardium of HF dogs and restored after chronic therapy with ELA. Normalization of mSTAT3 by ELA likely contributed to the observed improvement in MITO function following therapy with ELA in dogs with chronic HF.
Abstract 13016: Anticoagulation Control in Warfarin Treated Patients Undergoing Cardioversion for Atrial Fibrillation: A Pre-specified Ancillary Analysis From the ENSURE-AF Trial
Authors: Lip Gregory Y , Al-Saady Naab , Jin James , Sun Ming , Melino Michael , Winters Shannon M , Goette Andreas , Zamoryakhin Dmitry
Published: April 2024

Background:
In the ENSURE-AF study (NCT 02072434), the oral factor Xa inhibitor edoxaban was compared to warfarin in 2199 patients undergoing electrical cardioversion of nonvalvular AF. Ideal patient management requires optimization warfarin within a therapeutic range of INR 2.0-3.0. We determined aspects of anticoagulation control in the warfarin arm of this trial.

Methods:
In this multicenter, PROBE, parallel group Phase 3b clinical trial, we performed a pre-specified analysis of 1104 patients randomized to warfarin. We determined the Time to achieve Therapeutic Range (TtTR), Time in Therapeutic Range (TiTR), their clinical determinants and impact on outcomes. The primary safety endpoint was the composite of major + clinically relevant non-major (CRNM) bleeding from time of first administration of study drug to end of treatment +3 days. Patients were followed for 28 days on study drug after cardioversion + another 30 days to assess safety.

Results:
Among 1104 patients randomized to enoxaparin/warfarin, 27% were naïve to oral anticoagulants at randomization. Mean age was 64.2±11 years and mean CHA
2
DS
2
-VASc score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching INR 2.0-3.0 on warfarin was 70.8%. In 695 patients with INR <2 prior to first dose and who reached therapeutic range of ≥2, 436 had a SAMe-TT
2
R
2
score ≤2 and 259 a score of >2. Mean TtTR was 7.7 and 7.6 days, respectively. In 974 patients with INR in range of 2-3 post first dose, TiTR was 71.1% vs 70.3% for patients with SAMe-TT
2
R
2
score ≤2 and >2, respectively. On multivariate regression, an independent predictor of extended TtTR was CrCl (P=0.02). Independent predictors of TiTR were prior VKA experience (P<0.01) and low HAS-BLED score (P=0.02). TtTR was marginally related to stroke/SE/MI/CV mortality (P=0.06; OR [odds ratio]=0.23, CI 0.02-1.17) but not to any bleeding (P=0.53; OR=0.72, CI 0.28-1.80). TiTR was related to any bleeding (P=0.02; OR=0.39, CI 0.16-0.88), but not stroke/SE/MI/CV mortality (P=0.31; OR=0.42, CI 0.07-1.98).

Conclusion:
In this well-managed cohort of warfarin users in a clinical trial setting with a high TiTR (>70%), the SAMe-TT
2
R
2
score did not discriminate between mean TtTR and TiTR. Even in this short term study, TiTR was related to bleeding events.
Abstract 13062: Pathogenic IgG Antibodies in Hyperlipidemic Mice Promote Atherosclerosis
Authors: Kyaw Tin , Tay Chris , Kanellakis Peter , Cao Anh , Tipping Peter , Toh Ban-Hock , Bobik Alex
Published: April 2024

Background:
B2 cells promote atherosclerosis, but the exact mechanisms by which they promote atherosclerosis are not known. Antibodies can be pathogenic in a number of chronic inflammatory diseases. Here, we examined the role of antibodies in the development of atherosclerosis in hyperlipidemic mice.

Methods and Results:
As an interaction between B cells and CD4 T cells is important for plasma cell development and antibody production, we generated mixed chimeric LDLR
-/-
mice with B cells selectively deficient in MHC II or CD40 molecules. B cells deficient in either molecule decreased atherosclerosis by ~30-40%. This was associated with reduced spleen germinal centre B cells and plasma cells, markedly reduced plasma total immunoglobulins, reduced spleen CD4 T cell activation and decreased IFN-γ+ CD4 T cells. To confirm that the observed effects on atherosclerosis were largely due to impaired plasma cell generation and antibody production, we also deleted B cell-specific Blimp-1, a transcription factor critically important for B cell differentiation into antibody-producing plasma cells. Chimeric LDLR
-/-
mice transplanted with CD23
CRE
-Blimp-1
fl/fl
bone marrow were completely devoid of spleen plasma cells and plasma total immunoglobulins but CD4+ T cell activation was unaffected; atherosclerosis in these mice was reduced by nearly 50%. To exclude the possibility that the reduction in atherosclerosis was due to deletion of plasma cells, we then purified IgG from hyperlipidemic mice with atherosclerosis and transferred the IgG into immunoglobulin/plasma cell-deficient CD23
CRE
-Blimp-1
fl/fl
bone marrow transplanted LDLR
-/-
mice. Atherosclerotic lesions doubled in size in mice that received IgG from atherosclerotic mice, compared to transfer of IgG purified from non-atherosclerotic mice.

Conclusions:
Our study indicates that IgG antibodies generated in hyperlipidemic mice during atherosclerosis development accelerates growth of atherosclerotic lesions. Targeting pathogenic IgG antibodies in atherosclerosis has a potential to reduce lesion progression and the incidence of heart attacks and strokes.
Abstract 13128: Novel Markers and Tools for Early Assessment of CV Risk Beyond Framingham and ACC/AHA Guidelines
Authors: El Shahawy Mahfouz , Sabatini Antonella
Published: April 2024

Introduction:
Framingham risk score (FRS) has been widely used, despite its sub-optimal contribution for early CVD risk stratification, mainly in women. The ACC/AHA atherosclerotic cardiovascular disease (ASCVD) score has been recently introduced as an improvement to FRS for CV risk assessment.

Hypothesis:
The aim of this work was to assess if blood pressure rise post mild exercise (BPrisePME) and abnormal pro-BNP is an appropriate tool for early detection of structural and functional CV abnormalities in asymptomatic subjects.

Methods:
We screened 2406 asymptomatic subjects, age 20-79, for CVD risk using the Early Cardiovascular Disease Risk Scoring System (ECVDRS), which consists of 10 tests: large (C1) and small (C2) artery stiffness, blood pressure (BP) at rest and post mild exercise (PME), Carotid Intima Media Thickness (CIMT), abdominal aorta and left ventricle ultrasound (LVUS), retinal photography, microalbuminuria, ECG, and pro-BNP. Abnormal blood pressure rise post mild exercise (BPrisePME) was defined as systolic BP rise >30mmHg post 3-min-walk at 7% elevation, 2.5mph. Normotension (NT), pre-hypertension (pre-HTN), and hypertension (HTN) were defined according to JCN7 criteria.

Results:
Among the 2406 subjects, 1482 were in the age range 40-79, not taking any CV medication. These subjects, 841 female and 641 male, were stratified according to ASCVD, FRS and ECVDRS risk scores, respectively and assigned to low (L), intermediate (I) or high (H) risk. Prevalence of abnormal structural and functional abnormalities is in Table.

Conclusions:
Based on our data,

1. Abnormal rise in blood pressure prevalence correlates with the risks (L, I and H) in female and male, exhibiting structural and functional abnormalities.

2. ProBNP and BPrisePME are not statistically different in the ASCVD. and FRS underestimates the risk for female.

3. Abnormal rise and elevated ProBNP can help in the identification of early CVD and risk stratification in asymptomatic subjects.
Abstract 13166: Externally Irrigated Radiofrequency Ablation With Low Osmolarity Irrigant for the Treatment of Cardiac Arrhythmias
Authors: Jurgens Paul T , Tzou Wendy S , Zipse Matthew , Zheng Lijun , Sauer William H , Nguyen Duy T
Published: April 2024

Introduction:
Certain cardiac arrhythmias arise from deep or thick myocardium and may be refractory to standard external irrigated ablation. Externally irrigated ablation (EIA) is generally performed with normal saline (NS) as the infusing irrigant. Recent data suggest that larger ablation lesions can be created by decreasing the irrigant osmolarity.

Hypothesis:
We sought to evaluate the use of half normal saline (HNS) as the irrigant in externally irrigated ablation under
ex vivo
and
in vivo
conditions.

Methods:
Bovine myocardium was placed in a circulating saline bath in an ex vivo model. Two externally irrigated ablation catheters were oriented across from each other, with myocardium in between. Sequential unipolar ablations with HNS were performed at 50 Watts for 60 seconds, and ablation lesions were compared to using NS or HNS irrigation. In addition, a retrospective analysis was performed of all ablations using HNS completed at the University of Colorado from 2015-2016.

Results:
In vivo porcine ablations with HNS irrigation generated larger lesions, compared to control ablations using standard NS irrigation, and there was no increased incidence of steam pops (Figure 1). Clinically, 7 cases were identified that utilized HNS as the irrigant in EIA for refractory arrhythmias (1 atrial tachycardia, 6 VT/PVC cases). Acute success was achieved in 7/7 of procedures, with no recurrences at a mean follow up of 109 days. There were no complications (Figure 2).

Conclusions:
By decreasing irrigant osmolarity and charge density in EIA through the use of HNS, larger ablation lesions can be created to target deep arrhythmia circuits refractory to standard ablation.
Abstract 13225: Which Oral Anti-Coagulant Do Patients Prefer for Stroke Prevention in Non-Valvular Atrial Fibrillation?
Authors: Lip Gregory Y , Verdecchia Paolo , Tervonen Tommi , Ustyugova Anastasia , Heinrich-Nols Jutta , Gropper Savion , Kwan Ryan , Sri Bhashyam Sumitra , Marsh Kevin
Published: April 2024

Introduction:
There are various oral anticoagulants available for stroke prevention in patients suffering from non-valvular atrial fibrillation (NVAF) with some drug-related variations in clinical profile and non-clinical attributes. Patient preferences should be taken into account in anticoagulant prescription decisions.

Hypothesis:
Patient valuation of different anticoagulant characteristics in stroke prevention allows for meaningful comparison of the non-VKA oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and Vitamin K Antagonist (VKA, ie. warfarin).

Methods:
Multi-criteria decision analysis was developed with 5 clinical and 3 non-clinical criteria. Criteria weights were defined using results from two discrete choice experiments (DCEs). The evaluation model contained more fine-grained events than the DCEs, and therefore preference weights from DCEs needed to be distributed to the evaluation criteria. The weights were distributed according to event fatality rates, which were obtained from the RE-LY trial that compared dabigatran to warfarin. An additive model was used to combine treatment performance with the weights to estimate the overall value of each oral anticoagulant. Probabilistic and structural sensitivity analyses were performed.

Results:
Dabigatran obtained the highest overall value (see Figure: weighted contribution of different evaluation criteria to the overall value of five oral anticoagulants) and the highest first rank probability (88%) in the probabilistic sensitivity analysis. Rivaroxaban performed worse than the other NOACs, but better than VKA (both with 0% first rank probability). The results were insensitive to removing availability of reversal agent from the model.

Conclusions:
Patient preferences on treatment characteristics allows to discriminate oral anticoagulants for stroke prevention in NVAF, with dabigatran ranking highest and warfarin lowest.