bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15980: Effects of a Concurrent Strength and Endurance Training Program in Diabetes Patients a Randomized Controlled Trial
Authors: Bassi Daniela , Arakelian Vivian M , Mendes Renata G , Caruso Flavia C , Bonjorno Júnior José C , Arena Ross , Borghi-Silva Audrey
Published: July 2021

Background:
The prevalence of diabetes have increased globally to epidemic proportions; glycemic control and treatment remains a challenge. Concurrent aerobic and resistance training programs (CART) have been widely recommended as an important strategy to improve physiologic and functional performance.

Objective:
The impact of CART programs on metabolic profile, glycemic control and exercise capacity status in patients with diabetes requires additional study, which is the primary aim of the current study.

Materials and Methods:
We evaluated 41 patients (15 female and 19 male, 50.8±7 years) with a confirmed diagnosis of diabetes. The subjects were randomized in two groups: sedentary group (SG) and CART group (CART-G). CART was performed 12 weeks, 3 times a week for approximately 1 hour per session (30 minutes aerobic and 30 minutes resistance). Body habitus was assessed by body mass index, waist circumference, and skinfolds. Peripheral muscular strength was evaluated by an isokinetic dynamometer and pulmonary gas exchange was measured breath-by-breath, using a portable telemetric system during maximal incremental exercise testing on a cycle ergometer. Statistical analysis included Shapiro-Wilk test follow by ANOVA two way repeated measures.

Results:
We observed a decrease in HbA1c (8.1±1.6 to 7.3±1.2%), cholesterol (198.38.1±50.3 to 186.8±35.1 mg/dL) and HOMA IR (6.4±6.8 to 5.0±1.4) in the CART-G compared to the SG. There was no significant difference in fasting plasma glucose. Although body weight did not significantly change after training, skinfold measurements indicated decreased body fat in the CART-G only. CART significantly enhanced muscle strength (p<0.05) (peak torque: 135.5±4 to 159.7±47.7 N.m) compared to the SG (Peak torque: 145.3±47.9 to 143±42.2 N.m). CART was also associated with a significant increase in peak oxygen consumption, from 22.9±6.1 to 27.2±4.7 ml•kg
–1
•min
–1
compared to the SG, from 21.7±4.5 to 21±3.3 ml•kg
–1
•min
–1
as well as the maximal workload (124.6±29.1 to 149.9±29 watts) compared to the SG (123.6±36.9 to 122.1±32.9 watts).

Conclusion:
We concluded that CART is an important intervention strategy, producing both physiologic and functional improvements, in patients with diabetes.
Abstract 16009: Y RNA Fragments Enriched in Exosomes From Cardiosphere-derived Cells Mediate Cardioprotection and Macrophage Polarization
Authors: Cambier Linda , de Couto Geoffrey , Ibrahim Ahmed , Marbán Eduardo
Published: July 2021

Background:
Exosomes secreted by cardiosphere-derived cells (CDCs) are critical agents of regeneration and cardioprotection following ischemic injury, mediating the beneficial therapeutic effects of CDCs. Transfer of exosomal RNA to target cells is important for bioactivity.

Objective:
We sought to determine the RNA content of CDCs-secreted exosomes (CDC-exo), and to assess the contributions of selected small non-coding RNAs to the therapeutic efficacy of CDC-exo.

Methods:
Using next-generation sequencing (Illumina), we characterized the RNA content of CDC-exo. By direct transfection of fluorescently-labelled oligoribonucleotides, we delivered and tracked selected RNA fragments that are highly enriched in CDC-exo. In order to examine potential cytoprotective effects, neonatal rat ventricular myocytes (NRVMs) were pretreated with each of these fragments or a scrambled control fragment prior to H2O2-induced oxidative stress. Effects on gene expression were assessed by transfection of the fragments into bone marrow-derived macrophages.

Results:
Several noncoding RNA species were present in CDC-exo. Among these, Y RNAs (either whole or in fragments of the 5’ end) constituted 18% of all hits. From this data set, we selected two highly-enriched Y RNA fragments. Both fragments localized to the cytoplasm of CDC, NRVM and macrophages, and conferred augmented resistance to oxidative stress of NRVM (64.25±31.13% viability vs. 44±26.85%; p=0.06). Additionally, macrophages transfected with Y fragments exhibit rapid, robust polarization to a distinctive gene expression profile notable for upregulation of IL-10 (83.07 vs. 0.59 fold; p<0.0001), an anti-inflammatory cytokine.

Conclusions:
Here, we demonstrated that abundant noncoding RNA components of CDC-exo, Y RNA fragments, are bioactive components of CDC-exo. Two distinct fragments confer cardioprotection and also induce a strong anti-inflammatory response in macrophages. Although several components of the CDC-exo payload (including miRNA) contribute to functional efficacy, the present findings demonstrate the capacity of Y RNA fragments, an RNA species of previously-unknown function, to elicit therapeutic effects in vitro.
Abstract 16023: Physicians Feel Competent in Deciding When to Terminate Resuscitation but Have Limited Knowledge on Termination Guidelines and Rely on Unvalidated and Controversial Factors When Abandoning Resuscitation
Authors: Hansen Camilla , Lauridsen Kasper G , Schmidt Anders S , Løfgren Bo
Published: July 2021

Introduction:
Many resuscitation attempts do not succeed and have to be terminated. Several factors may influence the decision to terminate cardiopulmonary resuscitation (CPR) e.g. medical history, cause of cardiac arrest and anticipated prognosis. The aim of this study was to investigate self-assessed competence in terminating CPR and knowledge of the European Resuscitation Council (ERC) guidelines on termination of resuscitation. In addition, to evaluate single factors resulting in abandonment of CPR.

Methods:
Questionnaires were distributed to participants before advanced life support training at a university hospital. Participants included nurses and physicians serving as cardiac arrest team leaders and members from emergency, cardiology and intensive care departments. The questionnaire included questions on: 1) self-assessed competence in terminating CPR, 2) knowledge of ERC guidelines on termination of resuscitation, and 3) single factors resulting in abandonment of CPR. Data were collected from October 2014 through May 2015.

Results:
In total, 215 answers (response rate: 97%; 136 nurses and 79 physicians) were included in the study. Overall, 67% of physicians felt competent in deciding when to terminate CPR. No nurses and two (3%) physicians were able to state the ERC guidelines on when to terminate CPR. Physicians stated the following factors as single causes to terminate CPR: asystole for >20 min and no uncorrected reversible cause of cardiac arrest (75%), witnessed cardiac arrest without bystander CPR within 10 minutes (20%), cardiac standstill during echocardiography (19%), absence of pupillary light reflex during resuscitation (17%), age above 90 years (18%), known cancer (13%) and prolonged cardiac arrest with shockable rhythm (9%).

Conclusions:
Physicians feel competent in deciding when to terminate CPR. Knowledge on ERC guidelines for termination of resuscitation is limited. Physicians rely on unvalidated and controversial factors as sole ground for abandoning CPR.
Abstract 16064: Coronary Artery Calcification, Left Atrial, and Left Ventricular Size Measured From Non-contrast Cardiac CT Predict Incident Heart Failure Hospitalization in the General Population
Authors: Dykun Iryna , Lehmann Nils , Kälsch Hagen , Nöllen Isabelle , Geisel Marie Henrike , Möhlenkamp Stefan , Moebus Susanne , Jöckel Karl-Heinz , Erbel Raimund , Mahabadi Amir
Published: July 2021

Objective:
Non-contrast cardiac computed tomography (CT) is increasingly performed especially in the absence of known cardiac disease. We aimed to determine, whether CT-derived left atrial (LA), left ventricle (LV) size, and coronary artery calcification (CAC) are associated with future hospitalizations due to heart failure (HF).

Methods:
Subjects without known cardiac diseases from the population based Heinz Nixdorf Recall Study were followed for incident HF hospitalization. From non-contrast cardiac CT, LA and LV area were measured from axial images and indexed by body surface area. Cox regression analysis determined the association of each CT-measure with HF hospitalization in unadjusted and ASCVD-Score (atherosclerotic cardiovascular disease, pooled cohort risk equation) adjusted analysis. Hazard ratios (HR) and 95% confidence intervals are shown per standard deviation of LA/LV area and increase in log(CAC+1) by 1.

Results:
From 3944 subjects without known cardiac disease (59±8 years, 47% male, mean ASCVD-Score 11.3±10.8%), 31 subjects (0.8%) were hospitalized due to HF during 10.3±2.0 years of follow-up. LA index, LV index, and CAC-score were significantly associated with incident HF hospitalization in unadjusted analysis (LA: 3.24 [1.75-5.99], p=0.0002, LV: 5.65 [3.02-10.57], p<0.0001, CAC: 1.30 [1.12-1.51], p=0.0007). HRs remained significant for all three CT-measures after adjustment for ASCVD-Score (LA: 2.59 [1.36-4.94], p=0.004; LV: 4.19 [2.17-8.08], p<0.0001, CAC: 1.19 [1.01-1.40], p=0.042). Stratifying by age at baseline, association of LA and LV were stronger for younger subjects (<65 years: LA: 4.26 [1.91-9.49], p=0.0004; LV: 7.38 [3.23-16.88], p<0.0001; ≥65 years: LA: 1.40 [0.57-3.48], p=0.5; LV: 3.08 [1.13-8.36], p=0.03) while CAC-score was stronger in older subjects (<65 years: 1.07 [0.84-1.36], p=0.6; ≥65 years: 1.29 [1.01-1.65], p=0.041) in ASCVD-adjusted analysis.

Conclusion:
LA size, LV size, and CAC-score as measured from non-contrast cardiac CT are associated with incident HF hospitalization in the general population. Once cardiac CT is performed, quantification of LA and LV size may identify subjects at early and subclinical stages of HF that qualify for further cardiac workup, especially in younger age.
Abstract 16076: Cost-effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF vs. PREVAIL
Authors: Freeman James V , Hutton David W , Barnes Geoffrey D , Zhu Ruo P , Owens Douglas K , Garber Alan M , Go Alan S , Hlatky Mark A , Heidenreich Paul A , Wang Paul J , Al-Ahmad Amin , Turakhia Mintu P
Published: July 2021

Introduction:
Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown disparate results, and its cost-effectiveness compared to anticoagulation has not been evaluated using contemporary data.

Methods:
We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost-effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of PROTECT AF and PREVAIL randomized trials.

Results:
Using data from PROTECT AF, the incremental cost-effectiveness ratios (ICER) compared to warfarin and dabigatran were $20,140 and $24,400 per quality adjusted life year (QALY), respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (9.46, 9.59, and 9.64 QALYs, respectively) and more costly. At a willingness-to-pay-threshold of $50,000 per QALY, LAA closure was cost-effective 62% and 35% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation.

Conclusion:
The cost-effectiveness of LAA closure with the Watchman device depends largely on the clinical trial used for assigning event rates. Using data from PROTECT AF, Watchman was cost-effective; using PREVAIL data, Watchman was more costly and less effective than warfarin and dabigatran. Results were highly sensitive to the rates of stroke and intracranial hemorrhage in both treatment groups. Post-marketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
Abstract 16135: Hyponatremia is Related to Higher 30-Day Rehospitalization and 1-Year Mortality Rates in Patients Admitted With an Acute Coronary Syndrome: TRACE-CORE
Authors: Merchant Brendan C , McManus David D , Lessard Darleen , Gore Joel M , Goldberg Robert J , Kiefe Catarina I
Published: July 2021

Introduction:
Although hospital survival rates are improving among patients admitted with an acute coronary syndrome (ACS), early readmission is common and 1-year survival remains less than optimal. Improved risk stratification during an index ACS admission could direct greater surveillance or transitional care interventions for vulnerable patient populations prior to discharge from the hospital. While hyponatremia is associated with adverse outcomes after acute decompensated heart failure, less is known about whether hyponatremia relates to key post-discharge outcomes in patients discharged from the hospital after an ACS.

Hypothesis:
Hyponatremia is associated with early readmission and 1-year mortality in hospital survivors of an ACS.

Methods:
Using data from TRACE-CORE (Transitions, Risks, and Actions in Coronary Events - Center for Outcomes Research and Education), a diverse cohort of 2,081 patients discharged after an ACS, we examined the associations of admission hyponatremia (serum sodium ≤ 134 mmol/L) with 30-day readmission and 1-year all-cause mortality.

Results:
Cohort mean age was 61 (SD 11.3) years, 34% were women and 19% non-white. Hyponatremia was present in 10.9% and patients with hyponatremia had more pre-existing hypertension (p=0.002) and diabetes mellitus (p=0.001). GRACE scores and maximum troponin values were significantly higher in hyponatremic patients (p= 0.001 and 0.05, respectively). There was no significant difference in prior heart failure or home diuretic use between the two groups. Overall 1-year mortality was 4.58% and 30-day all-cause readmission rate was 13.46%. For patients with hyponatremia on admission, unadjusted odds of 30-day readmission were 36% higher (Odds Ratio 1.36, 95% CI 1.00 to 1.85) and 1-year mortality odds were almost 3-fold higher (Odds Ratio 2.79, 95% CI 1.71 to 4.55).

Conclusions:
Hyponatremia was associated with higher early readmission and lower 1-year survival. Serum sodium levels may represent a cost-effective biomarker of adverse post-discharge outcomes. The potential incremental prognostic information of serum sodium when added to existing readmission and post-discharge mortality risk prediction instruments should be investigated.
Abstract 16157: A TBX5 Driven Gene Regulatory Network Prevents Atrial Fibrillation
Authors: Nadadur Rangarajan D , Broman Michael , Boukens Bastiaan , Mazurek Stefan , Steimle Jeffrey , Bekeny Jenna , Efimov Igor , Weber Christopher , Christoffels Vincent , McNally Elizabeth , Moskowitz Ivan
Published: July 2021

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The genetics of AF are complex, but recent GWAS have revealed a number of AF risk loci, including
TBX5
.
TBX5
plays a critical role in heart development, and continues to be expressed in the adult atria. We assessed the role of
Tbx5
in the adult heart by removing
Tbx5
from the mouse at 6 weeks-of-age. Adult
Tbx5
mutant mice developed spontaneous sustained atrial fibrillation, characterized by surface electrocardiogram (ECG), intracardiac ECGs, and ex vivo whole heart optical mapping.
Tbx5
mutant isolated cardiomycytes showed prolonged action potentials, disrupted calcium handling, and abnormal automaticity.
Tbx5
mutant atrial gene expression analysis revealed down-regulation of numerous conduction system effectors genes including
Scn5a, Ryr2, Gja1, Atp2a2
,
Dsp
, and numerous potassium channels. We also observed
Tbx5
dependence of the transcription factor gene
Pitx2
, the number one locus associated with AF by GWAS. We identified an enhancer upstream of
PITX2
that interacts with the
PITX2
promoter by 4C and whose activity is TBX5 dependent and modulated by common SNP rs1906595, which alters a canonical TBX5 binding site. We also identified cis-regulatory elements at
Scn5a, Ryr2, Gja1, Atp2a2
, and
Dsp
, locus co-regulated by Tbx5 and Pitx2. We describe a TBX5-driven atrial molecular network including
Pitx2
that determines atrial conduction properties.
Abstract 16165: Embryonic Stem Cell-derived Cardiomyocytes Increase Viable Myocardium but Do Not Improve Function in a Mouse Model of Chagasic Cardiomyopathy
Authors: Carvalho Adriana B , Brasil Guilherme V , Silva-dos-Santos Danubia , Mesquita Fernanda P , Kasai-Brunswick Tais H , Cunha Sandro T , Goldenberg Regina S , Campos de Carvalho Antonio C
Published: July 2021

Chagas disease is a parasitic infection caused by
Trypanosoma cruzi
(
T. cruzi
). It is endemic in Latin America but cases have been increasing in the United States due to the migration of infected individuals. The objective of this work was to evaluate the effects of cell therapy with cardiomyocytes derived from mouse embryonic stem cells (CM-mESC) in a mouse model of chronic chagasic cardiomyopathy. CD1 mice were infected with the Brazil strain of
T. cruzi
. After 5 months, cardiac function was evaluated by magnetic resonance imaging (MRI) (Table 1). Left ventricular ejection fraction (LVEF) was decreased in infected animals when compared to non-infected controls, while LV end-diastolic volume (EDV) and LV end-systolic volume were increased. Right ventricular (RV) EF was not altered. However, RVEDV and RVESV were increased in the infected group when compared to non-infected animals. mESC E14TG2A line was differentiated into cardiomyocytes and efficiency was confirmed by troponin T staining. 8x10^5 CM-mESC were delivered by echocardiography-guided intramyocardial injection only if cardiomyocyte differentiation efficiency was above 70%. Cell tracking was performed by bioluminescence and MRI using luciferase-transduced cells and iron oxide nanoparticles, respectively. CM-mESC were detected in the heart for at least 8 days. After 45 days, MRI data showed no changes in LV or RV EF and volumes (Table 1). Sirius red staining was performed and the areas of viable myocardium and fibrosis were quantified by morphometry. Although no functional improvement was detected by MRI, there was a significant increase in viable myocardium when CM-mESC-treated mice were compared to placebo-treated animals. In conclusion, a single injection of CM-mESC in a mouse model of chagasic cardiomyopathy contributes to myocardial repair. However, this was insufficient to promote an improvement of cardiac function, which may require multiple cardiomyocyte injections.
Abstract 16188: Is Hypertrophic Cardiomyopathy Associated With Aortopathy: An Imaging and Epidemiologic Case Control Study
Authors: Ammar Khawaja Afzal , Ahmad Mirza Mujadil , Ahmad Mirza Nubair , Yousefzai Rayan , Krishnaswamy Janardhan , Khandheria Bijoy K , Jain Renuka , Tajik A. Jamil
Published: July 2021

Introduction:
A single prior case series has raised the concern that hypertrophic cardiomyopathy (HCM) and dilated aorta (DA) may be associated due to congenital or acquired reasons. This hypothesis has never been formally tested in prior research studies.

Hypothesis:
To evaluate the prevalence of DA in patients with HCM.

Methods:
We queried echocardiography database and electronic medical record system of our large tertiary care center for DA and HCM, respectively, over the last 4 years, in adults >15 years of age DA was defined as a sinus of Valsalva dilation (SVD), HCM was defined based on the presence of ICD 9 codes presence and cause- effect analysis was carried out with stratified analysis, followed by multivariate logistic regression analysis.

Results:
We found 553 patients with hypertrophic cardiomyopathy. In the echocardiography database, (SVD) measurement was available on 37,914 patients with 1035 patients with DA. The prevalence of DA was more than twice in those with HCM as compared to those without HCM (odds ratio 2.35; 95% confidence interval 1.33, 3.84; p value 0.001). This association persisted in stratified analyses for 28 causes of aortopathy, without meaningful confounding. This association persisted in a multivariate logistic regression model which included age, sex, diabetes, hypertension, dyslipidemia, smoking and aortic valve disease (odds ratio 1.87; 95% confidence interval 1.01, 3.14; p value 0.02). This association was higher in strength to that between aortic valve disease and DA (OR 2.35 vs.2.03).

Conclusions:
Our data support the hypothesis that HCM is associated with DA. The strength of association approaches other established causes of DA.
Abstract 16287: Effect of Transradial Catheterization on Patency Rates of Radial Arteries Used as a Conduit for Coronary Bypass
Authors: Ruzieh Mohammed , Moza Ankush , Diwan Pranav , Bangalore Bhavana S , Schwann Thomas , Tinkel Jodi L
Published: July 2021

Title:
Effect of transradial catheterization on patency rates of radial arteries used as a conduit for coronary bypass.

Objective:
To assess the difference in radial artery graft patency between patients who had the same radial artery used for angiography prior to bypass compared with those who did not. At present there are numerous studies looking at radial artery occlusion in situ after catheterization however very few studies looking at patency of the radial artery when used as a graft for CABG.

Methods:
A retrospective review was performed of all patients who underwent CABG at our institution in that past 15 years utilizing a radial artery graft (n= 570). Those who had subsequent imaging of the graft to evaluate patency by an angiogram or CT scan at any time were included for the study. 155 radial grafts were analyzed. The primary end point was evidence of occlusion at any point in follow up. Group A consisted of grafts in which the radial artery used for CABG had been utilized for angiography prior to CABG (n= 23). Group B consisted of grafts in which angiography was done via the femoral or contralateral radial approach (n= 132). Chi-square test was utilized to compare graft occlusion in these two groups. Statistical analyses was done using SPSS software.

Results:
The demographic characteristics of the patients in the two groups were similar. Occlusion of the radial artery graft was found to be more common in the group utilizing the same radial artery for angiography prior to CABG. The percentage of graft occlusion was 39 % (n= 9) in this group compared to 20 % in controls (n= 27). This difference showed a trend towards statistical significance with a p value of 0.05

Conclusion:
Radial artery graft patency appears to be adversely affected by its utilization for angiography prior to CABG. Other patient, procedural and management dependent confounding factors may also affect graft patency and should be investigated in larger scale or randomized studies.
Abstract 16290: Racial and Ethnic Differences in Heart Failure Progression in Post-menopausal Women: The Women’s Health Initiative
Authors: Breathett Khadijah , Foraker Randi , Abraham William T , Coker Laura , Leng Iris , Whitfield Keith , Shumaker Sally , Manson JoAnn , Eaton Charles , Howard Barbara V , Ijioma Nkechinyere , Cene Crystal , Martin Lisa , Johnson Karen , Klein Liviu
Published: July 2021

Background:
Heart failure (HF), a leading cause of morbidity and mortality in women, continues to disproportionately affect African-American (AA) women compared to women of other races/ethnicities. In a large cohort of post-menopausal women, we investigated if AA women progress through HF stages and coronary heart disease (CHD) death more rapidly than Caucasian (Cau) or Hispanic/Latina (HL) women.

Methods:
We assessed the American College of Cardiology/American Heart Association (ACC/AHA) HF stage A upon enrollment into the Women’s Health Initiative (1993-1998) and the progression from Stage A to Stage C, Stage C to CHD death, up to the last date of follow-up (2010). Cox proportional hazard regressions models were used to assess disease progression risk. We adjusted for age, baseline comorbidities, duration of comorbidities, interval development of myocardial infarction, ejection fraction at HF diagnosis, socioeconomic factors, and sex specific variables.

Results:
At baseline, AA women were younger and had a higher percentage of Stage A HF (76%) than Cau (54%) and HL (55%) women. Overall, AA and HL women had significantly lower risk of progressing from Stage A to Stage C compared to Cau women [AA vs. Cau adjusted Hazard Ratio (HR) 0.77 (95% Confidence Interval (CI) 0.64 -0.93) p = 0.0055; HL vs. Cau HR 0.54 (95% CI 0.40 -0.71) p < 0.0001]. After stratifying by age groups(<65, 65-69, >70 years), AA women had a similar risk of progression from stage A to C compared to Cau women. When compared to Cau women, AA had an insignificant increased risk of progressing from Stage C to CHD death [adjusted HR 1.29 (95% CI 0.72 -2.32) p = 0.3883)].

Conclusions:
Cau women were at higher risk for HF progression from Stage A to Stage C compared to HL women, but at similar risk as AA women. AA women had an insignificant but increased risk of progression from Stage C to CHD death compared to Cau women.
Abstract 16324: Genetic Predisposition Influences Anticoagulation Control and Major Hemorrhage Among Warfarin Users
Authors: Shendre Aditi , Brown Todd M , Liu Nianjun , Beasley T M , Hill Charles E , Limdi Nita A
Published: July 2021

Objective:
Genetic variants in Cytochrome P450 2C9 (
CYP2C9
) and Vitamin K epoxide reductase complex 1 (
VKORC1
) are recognized predictors of warfarin dose. However, their influence on percent time in target range (PTTR; INR range 2-3), overanticoagulation (INR>4) and risk of major hemorrhage have not been extensively evaluated. Herein, categorizing warfarin users possessing
CYP2C9 (*2,*3,*5,*6,*11)
and/or
VKORC1 (-1639
C>T) variants as sensitive responders, we evaluated whether sensitive responders (vs. normal) were more likely to have lower PTTR and a higher risk of overanticoagulation and major hemorrhage.

Methods:
The analysis included 1262 participants [310 sensitive responders (SR); 952 normal responders (NR)] in a warfarin pharmacogenetics inception cohort. The Rosendaal interpolation method was used to compute the PTTR, percent time above range (PTAR) and percent time below range (PTBR). Major hemorrhages included serious, life threatening and fatal bleeding events.

The influence of responder status (SR vs. NR) on PTTR, PTBR, and PBAR was evaluated using linear regression, and overanticoagulation and hemorrhage by Cox proportional hazards analysis adjusting for clinical factors.

Results:
Participants were followed for an average of 1.4 (± 0.9) years; with 1799 person-years (pyr) accrued. There was no difference in PTTR between SRs (54.4% vs. 53.8%, p=0.66) compared to NRs. However SRs had higher PTAR (20.3% vs. 16.7%, p=0.005) and lower PTBR (25.2% vs. 29.5%, p=0.01) and were more likely to experience over-anticoagulation (HR: 1.38, 95% CI: 1.23-1.56, p<0.001).

SRs had higher incidence of hemorrhage compared to NRs ((IRR: 1.48, 95% CI: 1.04-2.08, p=0.03). After adjusting for clinical factors, SRs remained at a higher risk for hemorrhage (HR: 1.81, 95% CI: 1.23-2.68, p=0.003).

Conclusion:
Warfarin users possessing
CYP2C9
and/or
VKORC1
variants are sensitive responders, spending higher percent of time above target INR range. These patients are more likely to experience overanticoagulation and major hemorrhagic events. Future research evaluating alterative treatment strategy including candidacy for the non-vitamin K antagonist oral anticoagulants is needed.
Abstract 16371: Targeted Delivery of Pulmonary Arterial Endothelial Cells Overexpressing Interleukin-8 Receptors Attenuates Liposaccharide-induced Lung Injury
Authors: Xing Dongqi , Giordano Samantha S , Gaggar Amit , Feng Wenguang , Chen Yiu-Fai , Creighton Judy , Oparil Suzanne
Published: July 2021

Background:
Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, there is still no effective therapy for ALI/ARDS, and treatment options are largely limited to supportive care. Neutrophil-mediated inflammation and endothelial cell (EC) injury are unifying features of the pathogenesis of ALI/ARDS. Interleukin-8 (IL8) receptors IL8RA and IL8RB (ILRA/B) on neutrophil membranes bind to IL8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and/or inflammation. This study tested the hypothesis that administration of rat pulmonary arterial ECs overexpressing IL8RA/B inhibits liposaccharide (LPS)-induced acute lung injury.

Methods and Results:
12-wk-old ovariectomized SD rats were divided into three groups and received intra-peritoneal (i.p.) injection of saline (Sham); LPS (Escherichia coli 026:B6, Sigma-Aldrich, 10 mg/kg, i.p.) followed by i.v. infusion of saline; or LPS followed by i.v. transfusion of ECs overexpressing IL8RA/B (IL8RA/B-EC, 2hrs post LPS), respectively. 6 hrs after LPS treatment, pro-inflammatory cytokine/chemokine mRNA levels were measured by real-time, RT-PCR in homogenates of right lung. Neutrophil infiltration and lung injury were assessed by immunohistochemical staining and H&E staining in tissue sections of formalin-fixed, paraffin-embedded left lung. Expression of mRNA for adhesion molecule (P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1), chemoattractant (cytokine-induced neutrophil chemoattractant-2 beta and monocyte chemoattractant protein-1), and pro-inflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) was markedly increased in lungs of LPS rats. Transfusion of IL8RA/B-ECs significantly attenuated expression of the pro-inflammatory mediators (by 50% to 70%) in LPS-injured lungs. Transfusion of IL8RA/B-ECs also significantly attenuated LPS-induced neutrophil infiltration and lung injury response.

Conclusion:
These provocative findings indicate that targeted delivery of ECs overexpressing IL8RA/B protects against LPS-induced acute lung injury.
Abstract 16386: Predicting Cardiac Arrest Myocardial Infarction (PreCAMI) in Out of Hospital Cardiac Arrest (OHCA) Survivors Lacking ST Elevations (STE)
Authors: Fitzgibbon James , Pike Francis , Dumas Florence , Scutella Michael , Kowalski Lindsey , Winger Dan , Wang Li , Rittenberger Jon , Mira Jean P , Elmer Jonathan , Toma Catalin , Callaway Clifton , Cariou Alain , Dezfulian Cameron
Published: July 2021

Introduction:
Coronary angiography (CA) and percutaneous intervention (PCI) after OHCA is recommended for suspected coronary occlusion based on ST elevation (STE) by ECG, yet 20-40% of OHCA patients without STE also have occlusions.

Hypothesis:
Clinical criteria available prior to CA can be used to create a score to predict whether PCI will be attempted in non-STE OHCA patients with sensitivity (Sn) and specificity (Sp) nearing STE. Attempted PCI in non-STE OHCA will be associated with improved survival and functional outcomes.

Methods:
We abstracted historical, demographic, resuscitation, ECG and lab data available within 6h of hospitalization in 156 non-STE OHCA who underwent early CA (<24h after OHCA). Logistic regression models tested associations between clinical variables and attempted PCI (model entry criteria p<0.1; stay criteria p<0.15). In these subjects and 304 non-STE OHCA who had delayed/absent CA, propensity adjusted regression examined associations of early CA (regardless of PCI attempt) or PCI attempt with survival or functional recovery (cerebral performance category 1-2, modified Rankin score 0-3 or discharge home or rehabilitation). Independent validation of score Sn and Sp was performed in a cohort where CA in non-STE OHCA is frequent (Cochin registry).

Results:
61/156 (39.1%) OHCA subjects without STE had attempted PCI. We derived a 4 variable (initial troponin, male sex, VF/VT presentation, epinephrine doses during CPR) parsimonious model (AUROC 0.78) which predicted PCI attempt with Sn 83%/Sp 51% comparing favorably to STE at our center (Sn 62%/Sp 77%). In Cochin 111/467 (24%) of CA resulted in PCI. Score validation in 407 OHCA with complete data yielded Sn 68%/Sp 50% for predicting PCI use in CA. Attempted PCI, but not CA alone, was associated with improved outcomes (US cohort). (
Table
).

Conclusion:
We've validated a 4 variable score which predicts PCI use in OHCA without STE. PCI use in this population is associated with improved outcomes.
Abstract 16432: Optimal Dosing of ACE Inhibitors and ARBs in Chronic Heart Failure Patients - A Meta-analysis of Randomized Controlled Trials
Authors: Malik Aaqib H , Akram Yasir , Malik Senada S
Published: July 2021

Introduction:
Congestive heart failure (CHF) is associated with significant morbidity and mortality. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are proven to be beneficial for improved survival and better quality of life in Heart failure patients. Optimal dosing of these agents presents a challenging question till date and controversy still surrounds whether similar health benefits can be achieved through lower dosages of ACE inhibitors and ARBs. Our aim was to determine whether there is a significant mortality benefit in CHF patients who receive higher dosage of ACE inhibitors and ARBs compared to lower dosage.

Methods:
Medline Indexed and Non-indexed, Cochrane Central, CINAHL and PsychINFO were searched for randomized controlled trials (RCTs) published till date. All RCTs that compared the clinical impact of high versus low dosage of ACE inhibitors or ARBs in heart failure patients were identified. Two independent investigators assessed the studies against an a priori inclusion criteria and disagreements were resolved by mutual discussion.

Results:
We used reported event rates for all studies to compute cumulative odds ratio and p-value for mortality. Summary effects were estimated using random effects models in RevMan 5.2. Of 1610 potentially relevant studies, a total of 5 studies (9027 patients) met our inclusion criteria and had data available on mortality events. The pooled estimate of the included studies showed a statistically significant 10% reduction in mortality of CHF patients who received higher dosage of ACE inhibitor and ARBs. (Odds Ratio: 0.90; 95% confidence interval 0.82,0.99). Heterogeneity was tested and it showed no evidence of publication bias.

Conclusions:
In conclusion, our meta-analysis of RCTs shows that higher dosage of ACE inhibitors and ARBs have a clinically and statistically significant mortality benefit over lower dosage in the management of chronic heart failure patients.
Abstract 16438: Serum Exosomal Protein Profiling for the Non-invasive Detection of Cardiac Allograft Rejection
Authors: Kennel Peter J , Maldonado Dawn , Givens Raymond , Brunjes Danielle , Castillero Estibaliz , Chen Emily , George Isaac , Mancini Donna , Schulze P. Christian
Published: July 2021

Introduction:
Exosomes are cell-derived vesicles in the extracellular environment present in biological fluids. Exosomal content is actively assembled containing mRNA, miRNA and proteins. Exosomal-derived molecules have messenger function on target cells.

Hypothesis:
The serum-derived exosomal proteome is altered in acute cardiac allograft rejection allowing a distinction between non-rejection and acute rejection episodes with specifics for the type of rejection.

Methods:
Serum samples were collected from heart transplant (HTx) recipients with no rejection (n=10), acute cellular rejection (n=10) and antibody-mediated rejection (n=8) confirmed by myocardial biopsy and histopathology report. Exosome isolation was performed using an isolation kit (Invitrogen). Proteomic analyses were performed by LC-MS/MS analysis using the Fusion Tribrid Orbitrap Mass Spectrometer. To confirm these findings, one of the proteins found by proteomic analysis, C1Q, was compared across samples with ELISA (Abcam).

Results:
A distinct pattern was detectable separating each group by clustering analysis. A exosomal protein signature totaling 24 proteins (FDR<2%) was found in the rejection group compared to the no rejection group. Further, patients with ACR had a distinctly different exosomal protein signature compared to patients with AMR. Of note, complement factor components such as C1QA (-53%), C1QB (-36%) and immunoglobulin subfractions such as IGHM (+42%) were the most significantly regulated proteins. Confirmatory ELISA testing of exosomal C1Q levels revealed a trend (p=0.077) towards decreased levels of C1Q in the AMR group but no significant difference in the ACR group.

Conclusions:
These data suggest a distinct exosomal proteome signature in cardiac allograft rejection patients as compared to patients without rejection, mainly involving complement cascade proteins, immunoglobulin fractions and structural proteins. Exosomal proteome analysis shows potential for non-invasive characterization of cardiac allograft rejection with distinct profiles in patients with ACR and AMR.
Abstract 16440: A Quantitative Appraisal of Recommendations Regarding Multi-vessel Intervention in ST-elevation Myocardial Infarction: Insights From the US Nationwide Inpatient Sample and an Updated Comprehensive Meta-analysis of Observational Data
Authors: Chatterjee Saurav , Yeh Robert W , Sardar Partha , Mukherjee Debabrata , Giri Jay
Published: July 2021

Introduction:
Current recommendations based largely on observational data state that multi-vessel percutaneous coronary intervention (MVPCI) in STEMI at time of initial hospitalization may be harmful.

Hypothesis:
MVPCI is not associated with higher in-hospital mortality in a large contemporary national dataset, and has never been.

Methods:
We queried the Nationwide Inpatient Sample (NIS) which includes in-hospital outcomes for 20% of all hospitalizations across US to identify mortality associated with MV-PCI for STEMI in unadjusted, multi-variable and propensity adjusted models. Published observational studies comparing in-hospital mortality with MV-PCI in contrast with infarct-related artery (IRA) only PCI were also pooled. Odds ratios (OR) and respective 95% confidence intervals (CI) were reported in a random effects model. Results were validated with study sequential analyses.

Results:
From 2009-2012-there were 11,454 MVPCI and 157,011 single-vessel PCI (SVPCI) for STEMI patients in the NIS. Mortality was 1.91% for MVPCI Vs 8.9% for SVPCI in the unadjusted analysis (OR 0.20, 95% CI 0.17-0.23). In a multivariable model(OR 0.28, 95% CI 0.24-0.33) and 1:3 propensity matched model (1.91% vs. 5.32%, OR 0.28, 95% CI 0.24-0.32)results were similar.

Our analysis of index hospitalization MVPCI versus infarct-related artery (IRA) - only PCI in the comprehensive meta-analysis of observational studies (19 studies, N=76,399), demonstrated no difference in in-hospital mortality with MVPCI (5.3%) compared with IRA-only PCI (5.06%)(OR 0.87, 95% CI 0.65-1.17; p=0.37).Study sequential analyses confirmed our results.(Figure)

Conclusion:
MVPCI is very rarely performed on the index hospitalization in a contemporary cohort of STEMI patients in the US reflecting adherence to current guidelines. Based on all available observational data, there does not appear to be early harm associated with MVPCI in STEMI.
Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing
Authors: Ware Stephanie M , Lipshultz Steven E , Colan Steven D , Shi Ling , Canter Charles E , Hsu Daphne T , Dodd Debra A , Everitt Melanie D , Kantor Paul F , Addonizio Linda J , Jefferies John L , Rossano Joseph , Pahl Elfriede , Rusconi Paolo , Schubert Jeffrey , Lee Teresa , Miller Erin , Tariq Muhammad , Wilkinson James D , Towbin Jeffrey A
Published: July 2021

Introduction:
Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing.

Hypothesis:
Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children.

Methods:
Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels.

Results:
The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation.

Conclusions:
Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.
Abstract 16488: Exploring the Functional Role of Exosomes in Stem Cell-mediated Cardiac Repair
Authors: Lang Jennifer K , Young Rebecca F , Ashraf Hashmat , Canty John M
Published: July 2021

Numerous experimental and clinical studies have shown a beneficial effect of cardiosphere-derived cell (CDC) therapy on regeneration of injured myocardium. Paracrine signaling by CDC secreted exosomes is hypothesized to be the principal mediator of improved function, however the mechanism of exosome uptake, cell specificity, and information transfer has yet to be elucidated. Our aim was to define the role of physiologically secreted human CDC-derived exosomes on cardiac fibroblasts, endothelial cells and cardiomyocytes by employing a knockdown (KD) strategy against nSMase2 and Rab27a, two genes crucial in exosome secretion.

Methods:
Human CDCs (hCDCs) were grown from atrial tissue biopsy explant culture and characterized by flow cytometry and immunocytochemistry. CDC-derived exosomes were isolated and characterized by particle size, immunoblot analysis and electron microscopy. Protein concentration of exosome preparations was quantified by Bradford microassay. nSMase2 and Rab27a shRNAi lentivirus was generated and used to create stable CDC knockdown lines. Co-culture transwell in vitro assays were designed to assess target cell proliferation, migration, angiogenesis, and fibrotic gene expression.

Results:
hCDCs expressed CD105, CD90, GATA4 and Nkx2.5, and were CD45 and cardiac troponin T negative. hCDC-derived exosomes were immunoreactive for CD63 and HSP90 and negative for Cyctochrome c and EEA1. shRNAi KD of nSMase2 and Rab27a resulted in successful blockade of exosome release from hCDCs. HUVECs co-cultured with scrambled shRNAi CDCs versus shRNAi nSMase2 KD CDCs showed increased angiogenesis and migration without affecting proliferation. While TGF-β stimulation of human cardiac fibroblasts significantly increased collagen I (COLI) and collagen III (COLIII) gene expression, there was no significant decrease in COLI or COLIII after treatment with exosomes.

Conclusions:
Secretion of hCDC-derived exosomes was effectively inhibited by nSMase2 and Rab27a lentiviral KD. Exosome release contributed to the angiogenic and pro-migratory effects of hCDCs but did not play a role in the fibrotic gene expression of human cardiac fibroblasts, suggesting a role for physiological exosome secretion in stem cell-mediated cardiac repair.
Abstract 16541: Abnormal Brain Connectivity and Poor Neurodevelopmental Outcome in Congenital Heart Disease Patients With Subtle Brain Dysplasia
Authors: Panigrahy Ashok , Votava-Smith Jodie , Lee Vincent , Gabriel George , Klena Nikolai , Gibbs Brian , Reynolds William T , Zuccoli Giulio , O'Neil Sharon , Schmithorst Vincent J , Paquette Lisa , Lo Cecilia W
Published: July 2021

Introduction:
Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments.

Methods:
The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained.

Results:
The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p<0.05), but not to specific heart lesions or white matter injury. Neurodevelopmental assessment of 20 patients at 18 months showed higher BDI score correlated with reduction in Total Developmental Quotient (p <0.05) and Adaptive Developmental Quotient (p<0.009).

Conclusion:
A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.