bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 20971: Associations Between Objectively Measured Sleep Duration and 10-Year Predicted Cardiovascular Risk in Older Adult Women
Authors: Full Kelsie M , Kerr Jacqueline , Song Dana , Malhotra Atul , Gallo Linda , Arredondo Elva M , Stone Katie , LaMonte Michael J , Stefanick Marcia L , LaCroix Andrea Z
Published: March 2022

Introduction:
In the US, 90% of women are living with one or more CVD risk factors, such as: high total cholesterol or hypertension, or lifestyle behaviors such as physical inactivity. Emerging evidence supports sleep duration, both short and long, as a potential modifiable lifestyle factor associated with CVD. Research on sleep duration and CVD risk is, however, limited by use of self-report sleep measures, homogeneous populations, and studies on individual CVD risk factors.

Hypothesis:
We examined the relationship between objectively measured sleep duration and predicted CVD risk, estimated by Reynolds Risk Score (RRS). We hypothesized that short sleep (<6 hours) and long sleep (>8 hours) would be associated with higher RRS compared to 6-8 hours.

Methods:
Cross-sectional data were analyzed in 1,316 racial/ethnically diverse older women, from the Objective Physical Activity and Cardiovascular Health Study, ancillary study to the Women’s Health Initiative. Women wore ActiGraph GT3X+ accelerometers on the hip for 24 hours over 7 days and completed a daily sleep log. RRS was calculated using data on age, sex, smoking, diabetes, hypertension, and high-sensitivity to CRP. Daily sleep duration was derived from accelerometer data. Adjusted linear regression models estimated the association of sleep duration and RRS. Participants were categorized as short (<6), healthy (6-8), and long sleepers (>8hrs/day) to account for non-linear associations with RRS. Adjusted means across categories were calculated using least-squares means procedure.

Results:
Results suggest a U-shaped relationship between sleep duration and RRS, with both short and long sleepers having significantly increased RRS compared to healthy sleepers (both comparisons p<0.01), with adjustments for BMI and race/ethnicity. Short and long sleepers had mean RRS of 15.7% and 13.6% respectively, compared to 11.2% among healthy sleepers. Results remained significant after further adjustments for education, self-rated health, and alcohol use.

Conclusions:
In older women, when compared to healthy sleep, actigraphy-ascertained short and long sleep durations are associated with increased 10-year estimated CVD risk, independent of adjustment for race/ethnicity, BMI, and known covariates.
Abstract 21021: Functional Regulatory Mechanism of Smooth Muscle Cell-Restricted
LMOD1
Coronary Artery Disease Locus
Authors: Nanda Vivek , Wang Ting , Iyer Dharini , Pjanic Milos , Liu Boxiang , Nguyen Trieu , Miano Joseph M , Quertermous Thomas , Leeper Nicholas J , Miller Clint L
Published: March 2022

Coronary artery disease (CAD) remains the leading cause of mortality and morbidity worldwide and has an estimated heritability of 40%. Meta-analyses of genome-wide association studies have now identified 73 genome-wide significant loci and the most recent multi-ethnic meta-analysis identified a number of arterial wall-specific loci. One of these loci include the smooth muscle cell-restricted factor, LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle tissues including main arteries and visceral organs of the gastrointestinal system. We hypothesized that LMOD1 may serve as a potent marker of the phenotypic modulation of smooth muscle cells during atherosclerosis.

We recently identified a non-coding regulatory variant, rs34091558, which is in linkage disequilibrium with the lead CAD GWAS variant, rs2820315 (P=7.7E-10; OR=1.05). However, the causal mechanism for how these variants alter LMOD1 expression/function and CAD risk remains unclear.

Expression quantitative trait loci (eQTL) mapping in GTEx and STARNET databases confirmed that rs34091558 is among the top eQTLs for LMOD1 in vascular tissues. Allelic expression imbalance analyses in heterozygous HCASMC donors further demonstrated cis-acting effects on LMOD1 gene expression. Position weight matrix (PWM) motif analyses identified the protective allele at rs34091558 to form a consensus forkhead box O3 (FOXO3) binding motif, which is predicted to be disrupted by the risk allele. FOXO3 chromatin immunoprecipitation and reporter assays demonstrated reduced FOXO3 binding and transcriptional activity by the risk allele in HCASMC. Platelet-derived growth factor BB (PDGF-BB) stimulation also significantly reduced LMOD1 expression coincident with FOXO3 knockdown. Finally, both gain and loss-of-function for FOXO3 and LMOD1 in HCASMC delineated a regulatory circuit by which LMOD1 decreased HCASMC proliferation and migration and increased cell contraction.

Taken together, these results provide compelling functional evidence that: 1) common genetic variation is associated with dysregulation of LMOD1 expression, and 2) changes in vessel wall processes through LMOD1 dysregulation may partially explain the heritable risk for CAD.
Abstract 21042: Cardiovascular Risk Stratification Using Off-the-Shelf Wearables and a Multi-Task Deep Learning Algorithm
Authors: Tison Geoffrey H , Singh Avesh C , Ohashi Daniel A , Hsieh Johnson T , Ballinger Brandon M , Olgin Jeffrey E , Marcus Gregory M , Pletcher Mark J
Published: March 2022

Introduction:
We aimed to evaluate whether a novel deep neural network (DNN) can predict cardiovascular risk factors from off-the-shelf wearables with a photoplethysmographic (PPG) heart rate sensor and accelerometer. Longitudinal heart rate variability and activity patterns have previously been associated with incident hypertension, diabetes, and sleep apnea, conditions which are frequently undiagnosed.

Methods:
Health eHeart, an IRB-approved UCSF study, enrolled 6,115 active users of the Cardiogram app for Apple Watch. Heart rate and step counts were collected for a period of 1 to 53 weeks (mean=8.9). Data from 70% of participants (33,628 person-weeks of data) was used to train a semi-supervised, multi-task DNN with both convolutional and recurrent layers to simultaneously predict prevalent hypertension, sleep apnea, and diabetes. Test performance characteristics were estimated using the remaining 30% of participants.

Results:
Mean age was 42.3 ± 12.1, 69% male. 2,230 (36.5%) of participants had hypertension, 1,016 (16.6%) had sleep apnea, and 462 (7.6%) had diabetes. In the validation set, the DNN outperformed a baseline logistic regression model incorporating age, sex, and beta blocker use, predicting prevalent hypertension with a c-statistic of 0.819 (95% CI 0.76-0.88; with an optimal operating point yielding 84.8% sensitivity and 63.6% specificity) vs a baseline c-statistic of 0.682 (95% CI 0.60-0.76), and prevalent sleep apnea with a c-statistic of 0.902 (95% CI 0.85-0.95; with an optimal operating point yielding 90.4% sensitivity and 59.8% specificity) vs a baseline c-statistic of 0.459 (95% CI 0.39-0.53). Results were not statistically significant for diabetes.

Conclusions:
Our DNN demonstrates surprisingly good prediction of hypertension and sleep apnea given that its only inputs are heart rate and step count. Whether such DNNs can provide durable and portable predictions for these conditions in other study samples is worth pursuing.
Abstract 21075: Heat Shock Factor 1 Modulates Exosomes Biogenesis and Cargo
Authors: Sharma Sudhish , Bigham Grace , Saha Progyaparamita , Mishra Rachana , Draggulin-Otto Sonia , Zachary-Brohawn Philip , Korutla Laxminarayan , Vallabhajosyula Prashanth , Karathanasis Sotirios , Kaushal Sunjay
Published: March 2022

Introduction:
Cardiac Progenitor cells (CPCs, identified by ckit+/CD45-/lin-) are being used in 21 clinical trials (recruiting and completed) to restore heart function and promote tissue regeneration in response to injury and their exosomes (EXO) has been identified to be critical for their functional activity.

Hypothesis:
We hypothesized that heat shock factor 1 (HSF1) modulates EXO biogenesis from CPCs and their enrichment with therapeutic miRs.

Methods and Results:
EXOs were isolated from cultured CPCs, generated from the biopsies of right atrial appendage (RAA) at the time of cardiac surgery from neonatal (nCPCs, < 1 month) and adult (aCPCs, > 40 years) patients with normal functioning myocardium using size exclusion chromatography (CL-2B). EXOs were analyzed by transmission electron microscopy, Nanosight (LM10) and the flow cytometry for EXO markers as CD63 and ALIX. Our results showed that physiological changes as ageing affects EXOs biogenesis and their functional potential as nCPCs generate significantly more EXOs than aCPCs. HSF1 overexpression in aCPCs significantly enhanced their EXO biogenesis. nCPCs derived EXOs (nEXOs) are significantly more effective (nEXOs 62.14±2.9% vs aEXO 56 ± 3.6%, p<0.05) to improve cardiac function and tissue repair in a myocardial infarction (MI) model in rats as compared to aCPCs derived EXOs. In a rat MI model, using florescent labelled HLA-A antibodies, nEXOs were identified to be retained for longer duration in rat serum as compared to aEXOs, which correlated with myocardial functional recovery. miRNA sequencing of EXOs identified significantly higher expression of cardio protective miRs like miR199a, 146a, 454, 590, 130a in nEXOs as compared to aEXOs. We also identified that HSF1 overexpression in aCPCs significantly enriched them with miR199a, miR130a and miR590 suggesting that HSF1 can affect EXO biogenesis and its miR Cargo. The results of large scale production of EXOs using hollow fibre systems will also be presented.

Conclusion:
We showed that nEXOs are functionally more active and modulation of HSF1 can affect EXOs biogenesis and its cargo from CPCs. These results also suggest that nEXOs has the potential to be utilized as an off the shelf cell-free therapy.
Abstract 21105: The Impact of Gestational Hypertension and Preeclampsia on Postpartum Rates of Follow-Up With Continuity Providers
Authors: Lewey Jennifer , Levine Lisa , Yang Lin , Groeneveld Peter
Published: March 2022

Introduction:
Pregnancy-related hypertension (PRH) is a risk factor for cardiovascular disease (CV) later in life and is associated with chronic hypertension after delivery. The early post-partum period is important for identifying at-risk women who would benefit from CV screening and therapies. The transition from obstetrical to long-term continuity care may not be seamless due to lack of PRH awareness and competing demands for time. We hypothesized that women diagnosed with PRH have low rates of follow-up with outpatient providers within 180 days after delivery.

Methods:
We used medical claims from a large national insurer from 2005 to 2013 to identify all pregnant women with PRH, as defined by diagnosis codes for gestational hypertension, preeclampsia, or eclampsia. We compared this cohort to two control cohorts: (1) pregnant women with chronic hypertension (CH) without PRH, and (2) pregnant women with neither CH nor PRH. Our primary outcome was any follow-up with outpatient providers within the 180 days following delivery.

Results:
We identified 495,814 completed pregnancies (see Table). Among the PRH cohort, gestational hypertension was most common (70%), followed by mild (44%) and severe (23%) preeclampsia. Women with PRH and CH had higher rates of coexisting chronic conditions compared to non-hypertensive controls, including diabetes, lipid disorders, and coronary artery disease. Rates of follow-up with primary care or cardiology providers were 26% in PRH cohort, 30% in CH cohort, and 19% in controls. Follow-up was slightly better with OB providers: 35%, 33%, and 32%, respectively.

Conclusions:
The peripartum period is an important opportunity to identify young women at higher risk for subsequent adverse CV events, yet the majority of women with either CH or PRH did not follow-up within 6 months after delivery. Low rates of outpatient follow-up may result in missed opportunities for CV risk reduction among these women, with subsequent higher CV incidence.
Abstract 21125: Long-Term Outcome of Administration of Hypoxia-Preconditioned Mesenchymal Stem Cells After Acute Myocardial Infarction in Nonhuman Primate Angiogenesis Persist for at Least 17 Months
Authors: Hu Xinyang , Xu Yinchuang , Li Qingju , Ni Chen , Kong Minjian , Zhang Fengjiang , Sun Jianzhong , Li Qian , Wu Yan , Zhong Zhiwei , Wang Jian’an
Published: March 2022

Rationale:
Hypoxia preconditioning (HP) could improve the effectiveness of bone marrow mesenchymal stem cells (MSCs) for cardiac repair. However, the long-term (>1 year) effects, potential arrhythmogenic complications of transplanted HP-MSCs are unknown.

Objective:
The present study was designed to assess the long term (17 months) outcome of HP-MSCs administration for the treatment of myocardial infarction (MI) in a small scale (N=10), nonhuman primate (Cynomolgous monkeys) investigation.

Methods and Results:
MSCs were engineered to express green fluorescent protein (GFP), cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then delivered into the infarcted hearts of Cynomolgus monkeys (1X10
7
cells per heart). 17 months later, HP-MSCs-treated monkeys tended to exhibited smaller scars, along with improvement of global left ventricular function. No ventricular arrhythmia were observed. It is worth mentioning that HP-MSCs transplantation triggered a prolonged response of angiogenesis, resulting in increased density of endothelial cells (CD31
POS
cells) and smooth muscle cells (SMA
POS
cells) for 17 months. However, HP failed to enhance the long-term retention of transplanted cells in the injured heart (No GFP
POS
cells were detected), indicating that the paracrine actions were the pivotal mechanisms of HP. Therefore, we further evaluated the therapeutic effects of exosomes, the major paracrine components, for the cardiac repair, and found that monkey HP-MSCs-derived exosomes injection displayed equivalent beneficial angiogenesis with HP-MSC per se administration for the treatment of MI in mice model.

Conclusions:
The beneficial effects of HP-MSCs on cardiac repair tended to be sustained for at least 17 months in non-human primates without increasing the occurrence of arrhythmogenic complications. This is the first report that administration of HP-MSCs in the heart induces angiogenesis via exosome secretion that persist for at least 17 months which support the safety and feasibility of HP-MSCs therapy.
Abstract 21156: Abo Status and Stroke Free Survival in Lvad Patients
Authors: Ilonze Onyedika J , Sane David , Phillips Stephen G , Shaver Katherine
Published: March 2022

Introduction:
Left Ventricular Assist Devices (LVAD) improve survival in selected patients. Complications include thromboembolism and bleeding. Alterations in von Willebrand factor (vWF) multimers may play a role, especially with continuous flow LVADs. AbO antigens are expressed on vWF where these antigens influence its processing into subunits. There are reports of higher bleeding rates in O patients and higher thrombosis rates in non-O patients.

Hypothesis:
ABO status is routinely determined prior to LVAD implantation and we correlated ABO status with outcomes. It may allow adjustment of anticoagulation to minimize adverse events.

Methods:
We studied adults with first implant of continuous axial LVAD entered into the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The implant operations occurred between the second quarters of 2012-2016. A total pf 6,462 patients were studied. A Cox proportional hazards model was analyzed using gender, age category, BMI, white race and blood type to predict the hazard rate of stroke or death after implant. Follow up was from time of implant until death, transplant, exchange, recovery, stroke or end of data set.

Results:
Increases in the hazard rate was seen in females (HR 1,26, 95% CI: 1.13-1.41; p<0.0001); age >50 (HR 1.62; 95% CI 1.42- 1.84; p<0.0001), and white race (HR 1.18; 95% CI: 1.06-1.31; p=0.002). Blood group O decreased the hazard rate compared to patients with non-O blood group (HR 0.92; 95% CI: 0.83-1.00; p=0.06).

Conclusions:
O blood group was associated with improved stroke free survival in multivariate analysis including gender, age category, BMI and race. This effect could be due to the lower levels of vWF in O blood group patients. Further work is being done to assess the effect of ABO blood group status on other thromboembolic events as well as bleeding outcomes. The impact of antiplatelet agents and anticoagulants on these outcomes will also need to be evaluated.
Abstract 21234: Patient and Lesion Predictors of Stenting and Atherectomy for Peripheral Arterial Disease
Authors: Ramkumar Niveditta , Suckow Bjoern D , Brown Jeremiah R , Goodney Philip P
Published: March 2022

Introduction:
Endovascular management of peripheral arterial disease (PAD) has become popular in the past two decades. But little is understood about the practice patterns of different endovascular treatment modalities and the factors that influence their use.

Objective:
Identify predictors for stenting and atherectomy treatment, compared to angioplasty (PTA) for PAD.

Methods:
We abstracted data from all endovascular procedures for PAD during January 2010- October 2016 in the Vascular Quality Initiative clinical registry. Adjusted logistic regression models built using backward elimination with a random-effects component for patient clustering were used to identify factors predictive of stenting or atherectomy compared to PTA at the artery level.

Results:
Eligible patients (n=58,231) had 106,039 arteries treated (median=2, IQR=1 to 3). The majority (50%) of these arteries were treated with stents, 39% with PTA and 11% with atherectomy. Compared to PTA, those receiving stents are more likely to smoke and have iliac treatment. In atherectomy, we see more distal treatment (SFA and tibial) compared to PTA. Artery location was a significant (p<0.05) effect modifier. In multivariable models, there were no significant predictors for atherectomy; TASC C trended to significance in femoropopliteal (OR 6.6 [p=0.08]) and tibial arteries (OR 11.1 [p=0.06]). TASC C and D predicted stenting in all arteries (Figure 1). Current smoking (OR 1.49 [1.32-1.68]), obesity (OR 1.30 [1.17-1.44]), and age 70-79 (OR 1.36 [1.07-1.17]) predicted stenting in femoropopliteal arteries. These factors also predicted stenting in tibial arteries: current smoking (OR 1.40 [1.04-1.88]), obesity (OR 1.50 [1.15-1.44]), and age 80-89 (OR 1.56 [1.14-2.17]).

Conclusion:
TASC C and D trended toward significance as predictors of atherectomy in tibial and femoropopliteal arteries. TASC C and D, artery type, smoking status, age, and obesity are significant predictors of stenting in all arteries.
Abstract 21293: Hypertension: Innovating Personalized Strategies for Excellent Results (HIPSTER)
Authors: Tison Geoffrey H , Pavlakos Rose , Sinha Tuhin K , Eslick Ian S , Coelius Rebecca , Gittelman Hannah , Schiller Nelson B , Stebbins Marilyn R , Kroon Lisa , Clinard Valerie , Olgin Jeffrey E , Grandis Donald , Rao Rajni K
Published: March 2022

Introduction:
In 2012, there were 39 million physician visits for hypertension (HTN), but only 53% of patients have hypertension under control. Remote management coupled with mobile health platforms may help improve communication, medication titration, care team feedback and patient experience. We conducted an observational study in order to evaluate the performance of mobile app-facilitated, team-based remote HTN management program on HTN control, time to control, and time spent under control.

Methods:
The HIPSTER study was an observational study conducted by the UCSF Division of Cardiology and School of Pharmacy in collaboration with Vital Labs Inc. We enrolled 120 consecutive patients from the UCSF Cardiology clinic who were aged ≥18 years with a diagnosis of essential or co-morbid HTN. Participants downloaded the Vital Labs smart phone application (app) and utilized a home blood pressure cuff to measure blood pressure at least once-daily. The app scheduled blood pressure reminders, allowed for virtual communication via direct messaging, and provided access to patient data. Based on the daily, remote BP measurements, pharmacists performed rapid-cycle medication management for patients remotely, in coordination with study cardiologists.

Results:
Of 120 patients enrolled, 59% were male, and 10% were between 18-35y, 43% between 36-64y, and 45% >64y. At the time of enrollment, 17.5% of patients were not on any antihypertensive medication. After 6 month follow-up, 84% of patients met their JNC8 goal. Patients took an average of 17 days to achieve BP control, and patients remained under control for 74% of the study duration.

Conclusions:
Using a mobile-app facilitated remote HTN management protocol, 84% of patients met their JNC8 BP goal, versus an estimated 53% nationally. Compared to prior reports that cite an average of 3.2 months to reach BP goal in real-world practice-based settings, patients in our study achieved JNC8 BP goal within 17 days from enrollment. A mobile app-facilitated remote HTN management platform, coupled with team-based care, can be used to increase achievement of BP control and decrease the time required to achieve BP control. Future directions include examining the generalizability of these findings through randomized studies.
Abstract 21294: Intrinsic Aerobic Capacity and Dynamic Exercise in Female Rats: Interaction on Early Vascular Remodeling in Hind Limb Ischemia
Authors: Zakari Madaniah , Durr Caitlin , Barefoot Katherine , Norvell Tyler , Alsahly Musaad , Koch Lauren , Britton Stephen , Katwa Laxmansa , Lust Robert M
Published: March 2022

Introduction:
The genotype associated with an inducible response to dynamic exercise is different from the genotype associated with the intrinsic capacity for aerobic exercise. The inducible response is an established component of rehab protocols after ischemic events, but the influence of the intrinsic capacity for exercise on the vascular response to active exercise following ischemic injury is unknown.

Hypothesis:
Reduced intrinsic aerobic exercise capacity will limit the early (2 week) inducible vascular response to active exercise after hind limb ischemia.

Methods:
Hind limb ischemic injury was created by unilateral femoral artery occlusion in previously established rat strains for high and low aerobic capacity phenotypes (HCR and LCR, Female, 40 weeks, n = 16 each). Beginning 3 days after the occlusion, 8 animals in each cohort began a 10 day, progressively increasing treadmill running protocol. Remaining animals served as sedentary post-ischemic controls. 14 days after occlusion, all animals were euthanized. Skeletal muscle was harvested from both hind limbs. Samples from the non-occluded contralateral hind limb were used as internal controls. All samples were stored in OCT at -80°C until processed for histologic assessment of capillarization (Rosenblatt staining).

Results:
LCR animals were about 80g heavier while HCRs had about 500% greater intrinsic running capacity (both p < 0.01). HCRs showed 26% better preservation of muscle fiber area in the post-ischemic limb, but LCRs increased fiber area with exercise at least 2 fold more with active exercise (p < 0.05). HCRs showed a greater increase (80%) in capillary density and perfusion exchange ratio (40%) in response to exercise. PCR for multiple angiogenic genes showed expression levels that were consistently higher in the LCRs, consistent with increased ongoing ischemic stress.

Conclusions:
Decreased baseline capillarization in the LCRs predisposed them to greater tissue loss following occlusion. The increased burden of exercise on the remaining fibers increased muscle growth in LCRs, but vasculogenic responses were delayed, despite stronger gene induction. Combining occlusion with exercise after occlusion in LCRs appeared to overwhelm the early angiogenic remodeling response.
Abstract 21312: Lactate Dehydrogenase A Affects Neutrophil Transcellular Extravasation by Upregulating Invadopodia Signaling
Authors: Sur Chowdhury Chanchal , Wareham Elizabeth , Xu Juying , Kumar Sachin , Hinge Ashwini , Dominique Filippi Marie
Published: March 2022

During inflammation, such as ischemia reperfusion injury or atherosclerosis, excessive neutrophil infiltration drives pathogenesis. Yet, the relationship between neutrophil transmigration and inflammation is ill-defined. Neutrophils migrate through endothelial cells (EC) via para (between EC) and transcellular (through an EC, TCM) mechanisms. During TCM, neutrophils interact with EC via invadopodia-like structures to form a ‘pore’ into EC membrane, thus facilitating neutrophil migration through EC body. We recently reported that deficiency in Rap1b, a member of RasGTPase superfamily, enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock. Rap1b-/- neutrophils exhibit increased TCM, invadopodia-like formation and metalloproteinase (MMP) release, suggesting mode of migration may influence inflammation outcome. Here, we used Rap1b-/- neutrophils to further investigate the link between neutrophil migration and inflammation. Using mass spectrometry, we found 2-fold increase in glycolytic enzymes hexokinase1, LDHA and PGK1, in Rap1b-/- protrusions compared to WT. Immunofluorescent staining and western blotting confirmed this observation. Inhibition of LDHA with a specific inhibitor FX11, inhibited Rap1b-/- invadopodia protrusions, MMP release and TCM. We then tested effects of LDHA inhibition on neutrophil transendothelial migration in vivo. Rap1b-/- and WT neutrophils were tagged with cell tracker dyes and transferred to recipient mice, treated with FX11 or DMSO control. Ear microvasculature was stimulated with FMLP and labeled with PECAM antibody to visualize EC junctions. More Rap1b-/- cells migrated out of vessels compared to WT cells at the same vascular environment. FX11 treatment significantly abrogated this increase. This suggests that LDHA and enhanced glycolytic metabolism play critical roles during transmigration in vivo perhaps by changing neutrophil migratory behavior and inflammation outcome. Since lactate, the glycolytic byproduct, induces milieu acidification and acidity play a major role in ischemic damage to the heart, our findings may be important for our understanding of cardiovascular injury and for the development of approaches for effective treatment.
Abstract 21321: Heart Rate During Pulseless Electrical Activity as a Marker for Successful Resuscitation and Neurological Outcome in a Rodent Model of Cardiac Arrest
Authors: Abbasi Hamidreza , Azadian Matine , Bazrafkan Afsheen , Bains Kajal K , Huang Zijia , Dinh Tin J , Kim Stephanie H , Nixon Tyler , Tian Guilian , Akbari Yama
Published: March 2022

Introduction:
During cardiac arrest (CA), a major goal of responders is to ascertain the likelihood of successful cardiopulmonary resuscitation (CPR) and optimize efforts accordingly to achieve return of spontaneous circulation (ROSC). Pulseless electrical activity (PEA), a common form of CA in inpatient settings, often allows monitoring of heart rate (HR) immediately preceding cardiopulmonary resuscitation (CPR). We were interested in assessing the role of HR during PEA in outcome of CPR. To evaluate this in a controlled setting, we used a rodent model of asphyxial CA with electrocardiogram (ECG) recordings and neurological testing. We hypothesized that more severe bradycardia may be associated with failure to achieve ROSC and worse neurological outcome if ROSC is achieved.

Methods:
Adult male Wistar rats (n=25) were anesthetized, intubated, and placed under mechanical ventilation. Needle electrodes were inserted into the rats to obtain continuous ECG data. Rats then underwent 8 minutes of asphyxial CA followed by CPR accompanied with intravenous epinephrine and bicarbonate injections. Neurological deficit scale (NDS) testing was conducted at 24hrs post-ROSC.

Results:
Of 25 rats that underwent CA, 4 failed to achieve ROSC. HR was measured after 7.5 minutes of asphyxia (i.e. 30 sec. prior to CPR), when the systolic blood pressure was <10-20mmHg, which is presumed to be a “pulseless” equivalent in humans. Rats failing to achieve ROSC had a significantly lower HR in comparison to rats achieving ROSC (26.6±8.4 vs. 46.2±16.9; p< 0.05). Interestingly, among survivors, HR immediately pre-CPR was inversely correlated with NDS scores (r=-0.655, p< 0.05). No association was found between groups in pre-CA arterial blood gas measurements (e.g. pH, CO2, electrolytes).

Conclusions:
In a rodent asphyxial model of CA mimicking a PEA state, rats failing to achieve ROSC had lower HR immediately prior to CPR. However, in rats achieving ROSC, slower pre-CPR HR is associated with better neurological outcome. These findings appear to be independent of respiratory acidosis. We propose a model and future experimentation that may help define underlying mechanisms. Validation is needed in human studies to assess potential translational implications in a clinical setting.
Abstract 21340: The Effect of Number and Level of Emergency Medical Technicians on Patient Outcomes Following Out of Hospital Cardiac Arrest
Authors: Lam Hio Cheng , Sun Jen-Tang , Chiang Wen-Chu , Hsieh Ming-Ju , Huang Edward Pei-Chuan , Sim Shyh-Shyong , Tsai Kuang-Chao , Lin Chih-Hao , Ma Matthew Huei-Ming
Published: March 2022

Introduction:
The effect of on-scene number and level of emergency medical technicians (EMTs) on the outcome of patients with out-of-hospital cardiac arrest (OHCA) remains unclear. In Taipei city, the respond number of EMTs for an OHCA ranged from 2 to 6 and the levels included EMT-intermediate (EMT-I) and EMT-paramedic (EMT-P).

Hypothesis:
We tested the hypothesis that for adult, non-trauma OHCA patient, on-scene EMT number more than 2 or level of the EMT-P ratio >50%, comparing to crews with two EMT-Is, would improve survival to hospital discharge.
Methods:
We analyzed five years of Utstein-based registry data on OHCA in Taipei. The eligible patients were non-traumatic adult OHCA with resuscitation attempts. The exposures were the total number of EMT or the EMT-P ratio >50%. The outcome was survival to discharge. Subgroup analyses were based on Utstein template.

Results:
From 2011 to 2015, there were 8,262 cases included. The average of on-scene EMT number was 3.0 ± 1.0, and a total of 1085 (13.1%) OHCAs was approached by crews of EMT-P ratio >50%. The overall cases of survival to discharge were 616 (7.5%). While the increase of one EMT on-scene was not associated with better chances of survival (adjusted odds ratio [aOR] 0.98; 95% confidence interval [CI]: 0.89-1.08), the level with the EMT-P ratio >50% was associated with improved outcome (aOR 1.36; 95%CI: 1.06-1.76). Subgroup analyses showed that EMT-P >50% significantly benefited the outcome in witnessed OHCAs with non-shockable rhythm (aOR 1.69; 95%CI: 1.01-2.58). Taking both number and level into consideration
(figure)
, the best survival to discharge occurred at 4 EMTs with the EMT-P ratio >50% (aOR 2.54; 95%CI: 1.43-4.50) when compared to crews with two EMTs.

Conclusions:
On-scene EMT-P ratio >50% was associated with improved survival to discharge of OHCAs, especially in those with witnessed, non-shockable rhythm. The presence of four EMTs with EMTP-ratio >50% at the scene of OHCA was associated with the best outcome.
Abstract 21349: Characteristics of Patients at Increased Risk of Serious Adverse Events While Receiving Intensive Blood Pressure Therapy: Post-Hoc Analysis of the SPRINT Trial
Authors: Fugar Setri , Okoh Alexis , Al-Ogaili Ahmed , Ayoub Ali , Vondee Noble , Desai Parth , Poudyal Abhushan
Published: March 2022

Background:
Intensive blood pressure management is associated with decreased overall incidence of myocardial infarction, stroke and hospitalization for heart failure among non-diabetic patients though with several associated adverse events (SAEs). The present study aimed to identify patients who are at increased risk of having adverse events while on the intensive blood pressure therapy.

Methods:
Data from the SPRINT trial was analyzed. Study participants who were in the intensive arm of the trial were divided into two groups based on the outcome of SAEs as defined per trial protocol. Baseline characteristics of the patients in both groups were compared using chi-square analysis. Logistic regression models were used to determine factors associated with developing a SAE while on the intensive therapy.

Results:
Out of 4678 patients who received intensive therapy, 1684 (36.0%) were females. The mean ± SD age was 67.9 +/- 9.4 years. The incidence of SAEs was 38.3% (n=1793). On multivariable analysis, factors associated with developing a SAE were found to Age (OR per unit change 1.04, 95% CI: 1.03-1.05 p-value: <0.001), Creatinine (OR/unit change 1.59, 95% CI: 1.12-2.26 p-value: 0.0094), Smoking (1.50, 95% 1.22-1.85, p-value:0.0001), BMI (OR/unit change 1.03,95% CI 1.02-1.04 p-value <0.001), urine microalbumin (numbers?) and the more medications the increased the risk of adverse outcomes.

Conclusion:
Intensive blood pressure management is associated with improved cardiovascular outcomes, however factors such as older age,high creatinine levels and a positive history of smoking are associated with developing serious adverse events. .
Abstract 21359: Safety of Repeat Radiofrequency Ablation in Atrial Fibrillation Patients With Moderate Pulmonary Vein Stenosis
Authors: Jazayeri Mohammad-Ali , Vuddanda Venkat , Pitchika Jaya , Gangireddy Mounika , Reddy Adla Jala Saisree , Lavu Madhav , Parikh Valay , Turagam Mohit K , Bommana Sudharani , Atkins Donita , Dendi Rhaguveer , Emert Martin P , Pimentel Rhea C , Sheldon Seth H , Berenbom Loren , Lakkireddy Dhanunjaya R , Reddy Madhu
Published: March 2022

Introduction:
Radiofrequency catheter ablation (RFCA), an effective treatment for atrial fibrillation (AF), is rarely complicated by severe pulmonary vein stenosis (PVS) requiring intervention. We sought to evaluate the safety of repeat RFCA in AF patients with moderate PVS after index RFCA.

Hypothesis:
We hypothesized, in patients with moderate PVS, repeat RFCA would not result in significant progression of PVS.

Methods:
We performed a retrospective, observational study of all patients who developed moderate PVS (decrease in the PV cross sectional area ≥50% but <75%) after index RFCA for AF. RFCA was performed with standard techniques for pulmonary vein antral isolation. All patients underwent CT scan of the heart with contrast prior to their first ablation and 3 months after each ablation procedure. Additional CT scans were completed per provider discretion in follow-up.

Results:
Of a total of 2550 AF patients who underwent RFCA from 2011-2016, 165 (6.4%) developed moderate PVS of at least one PV. Mean age was 65 ± 11 years, with 130 (79%) males and 113 (68%) with paroxysmal AF. Right superior, right inferior, left superior and left inferior PVs were involved in 31%, 29%, 41%, and 20% of patients, respectively. Of these 165 patients, 78 (47%) underwent repeat CT scan (with or without redo ablation), and 48 (29%) underwent redo RFCA in the antrum of the involved PV. Mean times between CT1-CT2 and CT2-CT3 were 6 and 11 months, respectively. On repeat CT, 6 (8%) developed severe PVS of at least one PV. There was no statistical difference in the incidence of severe PV stenosis between those who underwent repeat ablation compared to those who did not (4.2 vs. 14.3 respectively; p = 0.185)

Conclusions:
Repeat RFCA for AF in patients with prior moderate PV stenosis appears to be safe with an acceptable risk (4.2%) of developing severe PV stenosis.
Abstract 21415: Use of High Power Radiofrequency versus Low Power for Ablation of Atrial Fibrillation: Feasibility and Safety
Authors: Kheirkhahan Mobin , Baher Alex , Siebermair Johannes , Rechenmacher Stephen , Kaur Gagandeep , Steinberg Benjamin A , Chelu Mihail G , Han Frederick T , Marrouche Nassir F
Published: March 2022

Introduction:
Radiofrequency Catheter ablation (RFCA) has become an established strategy to treat symptomatic and drug refractory cases of Atrial Fibrillation (AF). Despite its safety, RFCA accompanies some serious complications such as esophageal thermal damage, that makes physicians more cautious while ablating the posterior structures and avoid using higher powers for RFCA.

Hypothesis:
We aim to investigate the safety of 50 watts RFCA compared with 35 watts, by the novel method of detecting any esophageal enhancement with Late Gadolinium Enhancement MRI (LGE-MRI).

Methods:
Records of 511 AF patients from 2012 to 2016 were collected; who underwent RFCA and had LGE-MRI post-ablation to detect any esophageal injury. The method of ablation for both groups includes Pulmonary Vein Isolation (PVI) and Posterior Wall Debulking (PWD). Patients were categorized into 2 groups: The High Power (HP) group who underwent ablation with 50 Watts catheters and the Low Power (LP) group, for whom the 35 Watts catheters were used. With regard to their respective esophageal enhancement, patients were classified as those who had no, mild, moderate, or significant esophageal enhancement.

Results:
There were 459 patients in HP group (301 men; mean age 70.4 ± 11.2) and 52 patients in LP group (32 male; mean age 64.1 ± 11.7). HP group was significantly older (p < 0.05) and persistent type of AF was more common among them (51.5% vs 25%, p < 0.05). The incidence of esophageal enhancement post-ablation was not significantly different among HP and LP groups (Figure 1) but the procedure time was significantly shorter for HP group (149.3 ± 64.8 minutes vs 308.4 ± 104, p < 0.001). None of our patients (in both groups) developed serious complications such as atrioesophageal fistula.

Conclusions:
Using high power radiofrequency catheter ablation for AF patients shows no correlation with esophageal enhancement post-PWD ablation, furthermore they can significantly reduce the procedure time.
Abstract 23077: The Effects Of Prolonged Anacetrapib Therapy On First And Subsequent Occlusive Vascular Events
Authors: Sammons Emily , Bowman Louise , Landray Martin ,   on behalf of the REVEAL Study Collaborative Group
Published: March 2022

Background:
There is definitive evidence that lowering LDL-cholesterol with statins as monotherapy, or in combination with ezetimibe or PCSK9 inhibitors, prevents not only first but also subsequent major coronary events (i.e. coronary death, myocardial infarction or coronary revascularization). Consequently, prolonged treatment produces greater absolute reductions in morbidity, mortality and economic costs. Inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib lowers LDL-cholesterol levels, as well as substantially increasing HDL-cholesterol, but it is not yet known if it produces benefits on first and subsequent occlusive vascular events and deaths.

Methods:
The HPS3/TIMI55-REVEAL trial has assessed the effects of adding the CETP inhibitor anacetrapib to atorvastatin on vascular morbidity and mortality in 30,449 individuals who had a history of atherosclerotic vascular disease. Study treatment was continued for a median of 4.1 years. Information was recorded on first and subsequent cardiovascular events that occurred during the scheduled treatment period.

Results:
The main trial results are to be presented at the European Society of Cardiology Congress in August 2017. For the American Heart Association Congress, it is proposed to present more detailed results on the effects of anacetrapib on first and subsequent occlusive vascular events. Within this high-risk population of individuals with pre-existing vascular disease, 3443 (11%) had a first major coronary event and 1097 subsequent events were reported during the scheduled treatment period.

Conclusions:
Unblinded results of the cumulative effects of anacetrapib on first and subsequent rates of coronary and other occlusive vascular events will be available for presentation.
Abstract 23079: Clinical Outcomes of Transcatheter Mitral Valve Replacement for Degenerated Mitral Bioprostheses (Mitral Valve-in-Valve) and Surgical Rings (Mitral Valve-in-Ring) in the United States: Data From the STS/ACC/TVT Registry
Authors: Guerrero Mayra , Wang Dee Dee D , Vemulapalli Sreenkanth , Xiang Katelyn , Salinger Michael , Eleid Mackram , Greenbaum Adam , Kodali Susheel , George Isaac , Whisenant Brian , Pershad Ashish , Fang Kenith , Coylewright Megan , Shah Pinak B , Thourani Vinod , Babaliaros Vasilis , Tommaso Carl , Saucedo Jorge , Kar Saibal , Makkar Raj , Leon Martin , Rihal Charanjit , O'Neill William , Feldman Ted
Published: March 2022

Introduction:
Transcatheter mitral valve replacement (TMVR) using aortic transcatheter heart valves (THV) is developing as an alternative to surgery for patients with severe mitral valve disease due to degenerated mitral bioprostheses or failed surgical rings who are poor surgical candidates. Outcomes of off-label procedures in the United States are being collected in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry. A comprehensive analysis of mitral Valve-in-Valve (VIV) versus Valve-in-Ring (VIR) outcomes has not previously been performed.
Objectives:
To evaluate in-hospital and 30-day clinical outcomes of mitral VIV and VIR procedures in the United States.

Methods:
Retrospective analysis of data from the STS/ACC TVT Registry on patients who underwent mitral VIV or VIR procedures.

Results:
587 patients underwent TMVR VIV (n=494) or VIR (n=93) procedures between January 2013 and December 2016 at 144 hospitals. Median age was 76 (VIV) and 73 (VIR) years, (p=0.024), 60.9% (VIV) and 44.1% (VIR) were female (p=0.003), median left ventricular ejection fraction was 55% in VIV and 50% in VIR (p <0.001), and median STS score was 10.5% (VIV) and 9.2% (VIR), p=0.131. Transseptal access was utilized in 35% VIV and 46.2% VIR procedures, p=0.081. Procedural success was achieved in 74.4% of VIV and 57.8%VIR (p=0.239). Left ventricular outflow tract (LVOT) obstruction was more common in VIR (5.4%) vs VIV (0.06%), p=0.003. Post-procedure median mean mitral valve gradient was 4mmHg in both groups. 95.7% of VIV and 86% of VIR patients had post-procedure mitral regurgitation ≤1(+), p<0.001. In-hospital mortality was 6.9% for VIV and 9.7% for VIR (p=0.343). 30-day mortality was 9% for VIV and 12% for VIR (p=0.387). At 30-day follow up, 85.6% of VIV and 77.7% of VIR patients were in New York Heart Association class I or II (p=0.398).

Conclusions:
TMVR VIV and VIR using aortic transcatheter heart valves in high surgical risk patients are associated with similar in-hospital and 30-day mortality and symptom benefit. LVOT obstruction post-TMVR and residual mitral regurgitation ≥2 (+) were more frequent in VIR procedures. The long-term effect of these procedures is not known and requires further evaluation.
Abstract 24034: MFG-E8 Fragment Medin and Arterial Aging
Authors: wang yushi
Published: March 2022

Background:
Aging increases milk fat globule EGF-VIII (MFG-E8) expression in the rat, nonhuman primate and human aortic walls, facilitating the invasion, proliferation, and proinflammation of vascular smooth muscle cells (VSMCs). The MFG-E8 C-terminal fragment medin has been reported to be involved in the necrosis of VSMCs at the inflammatory sites of aortic dissection, however, its cleavage processes, aortic wall levels with aging and bio-role in VSMCs remains to be determined.

Material and Methods:
In this study, immunofluorescence, immunohistochemistry and western blot analysis demonstrate that MFG-E8 and its fragment medin (
Figure
), activated matrix metalloproteinase type II (MMP-2) and platelet derived growth factor receptor type-beta (PDGFR-β) protein levels were markedly increased in human grossly normal aortic walls from old (n=10, >50 yrs) vs. younger donors (n=10, <25 yrs). Importantly, exposure of medin peptide (20 to100nM) to primary cultured VSMCs isolated from young (8 mo) and old (30 mo) FXBN rat aortae significantly increased MMP-2 activation, PDGFR-β expression, and migratory capacity measured by a modified Boyden chamber in a dose-dependent manner in both also. Separate exposure of activated MMP-2 to recombinant human MFG-E8 protein and also to MFG-E8 enriched old human aortic protein markedly increased the cleavage product medin in both, which was substantially inhibited by an MMP inhibitor, GM6001. Exposure of medin to VSMCs did not significantly affect the expression of cell cycle related proteins. In addition, PDGF-BB treatment markedly activated MMP-2 in both young and old VSMCs, which was substantially reduced by a PDGFR-β inhibitor, RTK.

Conclusion:
Taken together, targeting MFG-E8 or its cleavage product medin is a novel approach to the prevention or treatment of large arterial aging or age-associated disease.
Abstract 24068: Developing a Cardiomyocyte Pipeline for Gene Edited hiPSCs
Authors: Gerbin Kaytlyn , Nelson Angelique , Roberts Brock , Arakaki Joy , Grancharova Tanya , DeLizo Colette , Gunawardane Ru
Published: March 2022

The Allen Institute for Cell Science (AICS) is creating an open source collection of fluorescently tagged human induced pluripotent stem cell (hiPSC) lines to model cell organization and dynamics of stem cells and differentiated hiPSC-cardiomyocytes. Understanding the sub-cellular organization and the structure/function relationships of organelles within cardiomyocytes will contribute to the development of better disease models, therapies, and regenerative medicine approaches for cardiac disease. Using the WTC human iPSC line and the CRISPR/Cas9 system, we have fluorescently tagged ~20 target genes representing key cellular organelles including a few cardiac-specific genes. Edited iPSC lines are differentiated into cardiomyocytes using established protocols with either small molecules or a combination of cytokines and small molecules, which produce high-purity monolayers of beating cardiomyocytes within 1-2 weeks. Differentiation into cardiomyocytes serves as an important quality control criterion for our gene editing efforts, but also comprises an important aspect of our predictive cell modeling efforts. We plan to study the changes in localization and organization of these tagged organelles as the stem cells differentiate into cardiomyocytes using live fluorescent cell imaging. Here, we present our cardiac differentiation methods for multiple edited hiPSC lines and the quantitative and qualitative assays used to determine the efficacy of differentiation, including myofibril contraction, cardiac protein expression, and transcriptome profiling by bulk and single cell RNAseq. Additionally, we confirm the localization of cardiac proteins such as troponin T and alpha-actinin to the myofibrils in differentiated cells using image-based assays. In experiments initiated to date we have successfully differentiated multiple gene edited iPSC lines representing major cellular structures, 2 of which are specific to cardiomyocytes (ssTNNi1 and ACTN2). Some of the gene edited hiPSC lines are fluorescently-tagged for structures including focal adhesions, actin and microtubule cytoskeleton, mitochondria, nuclear envelope, desmosomes, and endoplasmic reticulum, which are all publically available to the community.