bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P196: A Large Genetic Effect of APOC3 A43T SNP on Serum Triglycerides is Mediated by Serum APO-CIII Levels in Amerindians
Authors: Hsueh Wen-Chi , Walter Mary F , Nair Anup , Hanson Robert L
Published: July 2021

Introduction:
Using a population-based linkage analysis approach, we previously identified a major locus for serum triglyceride (TG) levels in Pima Indians, which largely reflects the effect of a functional SNP (p.(Ala43Thr), A43T, or rs147210663) in the APOC3 gene. This non-synonymous SNP is extremely rare in non-Amerindian populations and more common in the Pima Indians (frequency of the T43 allele≈3%). This SNP alters the structure of APO-CIII, which leads to loss of its function and to lower circulating levels of APO-CIII. Its effect size reduces TG level by approximately 1 SD unit (per allele), which is among the largest effects for any complex trait reported to date.

Hypothesis:
To further explore the functional mechanism underlying this association, we analyzed the relationships among A43T, TG and APO-CIII levels; we hypothesized that the
APOC3
A43T SNP effect on TG is mediated through circulating APO-CIII in the blood.

Methods:
We measured serum APO-CIII level in 411 randomly selected Amerindian subjects from a larger cohort study with both the A43T genotype and TG levels measured; this included 22 carriers of a T43 allele (frequency=2.7%). All analyses were modeled using linear regressions based on cross-sectional data, with age, sex, diabetes status, and population admixture included as covariates. The natural logarithms of APO-CIII and TG levels were taken to reduce skewness.

Results:
The phenotypic correlation between APO-CIII and TG was 0.68. We found a strong association between the A43T SNP and TG levels (β=-0.78±0.21 SD unit per copy of the T43 allele, p=0.00026, explaining 3.2% variance) that was greatly attenuated with further adjustment for APO-CIII levels (β=-0.04±0.17 SD unit, p=0.81, explaining 0.01% variance). On the other hand, there was also a strong association between the A43T SNP and APO-CIII levels (β=-1.22±0.21 SD unit, p=1.2х10
-7
, explaining 6.5% variance), which remained significant even after adjustment for the TG effect (β=-0.61±0.16 SD unit, p=0.00016, explaining 3.4% variance). Formal mediation analysis, conducted by the Sobel method, suggested significant and virtually complete mediation of the A43T effect on TG through APO-CIII levels (p=5.2х10
-7
, percent mediation=95%).

Conclusion:
Our results suggest that the
APOC3
A43T SNP effect on TG may be primarily mediated through APO-CIII, and lend further strength to the possibility of making APO-CIII a therapeutic target for CVD interventions. We are in the process of expanding our analysis to a much larger sample.
Abstract P200: Elevated Triacylglycerols and Diacylglycerols Had Association With Increased Carotid Arterial Stiffness, Independent of Cvd Risk Factors, in Women With or at High Risk of HIV Infection
Authors: Quispe Renato , Hua Simin , Clish Clary , Scott Justin , Deik Amy , Hanna David B , Anastos Kathryn , Garcia Mario J , Kaplan Robert , Kizer Jorge R , Qi Qibin
Published: July 2021

Background:
Metabolomics has provided new insights into mechanistic knowledge of CVD. However, this approach has limited use for studying arterial disease in high-risk women with and without HIV infection.

Methods:
Using liquid chromatography-tandem mass spectrometry, we profiled plasma levels of 114 cationic polar and 211 nonpolar lipid metabolites among 411 women (72% HIV+; 60% Black and 31% Hispanic) aged 35-50 from the Women’s Interagency HIV Study. Carotid arterial distensibility, a direct measure of carotid stiffness, was calculated from ultrasound measurements of the right common carotid artery diameter at systole and diastole and brachial artery pulse pressure measured. We performed partial least squares discriminant analysis (PLS-DA) to identify metabolite clusters associated with carotid stiffness (lowest vs. the other 3 quartiles of distensibility index). We used multivariate linear regression models to examine associations of individual metabolites with the distensibility index.

Results:
PLS-DA identified two major metabolite clusters associated with carotid stiffness. In the lipid metabolite cluster, triacylglycerols (TAGs 52:3, 52:4, 54:4), diacylglycerols (DAGs 36:2, 36:3) and sphingomyelins (16:1, 18:1, 18:2) were associated with decreased distensibility, while lysophosphatidylcholines (18:2, 20:5) were associated with increased distensibility. In the cationic polar metabolite cluster, urate, C4-OH carnitine, C5-DC carnitine, pseudouridine and 1-methyladenosine were associated with decreased distensibility. The associations of TAGs 52:3, 52:4, 54:4 and DAG 36:3 with carotid stiffness remained significant after further adjustment for conventional CVD risk factors (
Table
). No interaction by HIV infection was found.

Conclusions:
Among women with or at risk of HIV infection from predominantly race-ethnic minority groups, plasma TAGs and DAG of higher carbon number and double bond content are associated with carotid stiffness independent of conventional CVD risk factors.
Abstract P207: An Interpretation-Friendly Approach for Model Comparison of Risk Scores for Adult Obesity in the International Childhood Cardiovascular Cohort (I3c) Consortium
Authors: Hu Tian , Sinaiko Alan , Woo Jessica , Burns Trudy , Steinberger Julia , Bazzano Lydia , Urbina Elaine , Zhang Nanhua , Magnussen Costan , Venn Alison , Juonala Markus , Raitakari Olli , Daniels Stephen , Dwyer Terence , Jacobs David
Published: July 2021

Introduction:
Continuous Net Reclassification Improvement (NRI) compares risk prediction between 2 models, but the NRI scale is hard to interpret as a difference of differences of correct vs. incorrect reclassification. We developed Discrimination Improvement Analysis (DIA), a mathematically-related alternative. We illustrate DIA in i3C comparing P(adult obese) estimated from childhood either using body mass index (BMI; base model) or BMI percentile (CDC Chart 2000; alternative model).

Methods:
In both DIA and NRI (described in the Table), reclassification is based on the regression discriminant to assess reclassification up when predicted risk is increased under the alternative model (>0), and down when the opposite is true (≤0). The DIA metric is the “added spread”: observed P(adult obese) in those reclassified up minus in those reclassified down. Using Bayes rule, continuous NRI is a weighted average of the P(adult obese) in those reclassified up vs down. We used first childhood BMI (age 3-19 y) and last adult BMI (age 30-50 y) in i3C. Logistic regression estimated P(adult obese) in the base model and the alternative model.

Results:
Of 8864 participants (47% men, 89% white, mean child BMI age 11 y (SD 4), mean adult age 38 y (SD 6)), 2436 were obese adults (last adult BMI≥30 kg/m
2
). Both absolute BMI and BMI percentile were independent predictors (Table). Average P(adult obese) in the base model was 24.1%. The alternative model significantly added spread of 11.2%: observed P(adult obese) 30.2% in those reclassified up vs 19.0% in those reclassified down, P<0.001). Using the continuous NRI yields a result qualitatively similar to DIA: 0.28 (95% CI: 0.25, 0.31).

Conclusions:
The DIA and NRI agreed that prediction of P(adult obese) was improved using BMI percentile over using absolute BMI, although DIA and NRI may disagree due to different weighting. The DIA method of quantifying added spread in prediction has the advantage of being on the natural scale. The DIA principle may also be applied to a continuous dependent variable.
Abstract P227: Circulating and Dietary Linoleic Acid and Prevalent Diabetes in Post-Myocardial Infarction Patients
Authors: Pertiwi Kamalita , Wanders Anne J , Zock Peter L , Harbers Marjolein C , Geleijnse Johanna M
Published: July 2021

Background:
Circulating linoleic acid 18:2n-6 (LA) has been considered to reflect LA intake, but its utility as a dietary biomarker could be affected by metabolism.

Objective:
To study the associations of plasma and dietary LA with T2D prevalence in drug-treated patients with a history of myocardial infarction (MI).

Methods:
Cross-sectional analysis of baseline data in 4,072 Dutch post-MI patients of the Alpha Omega Cohort. Circulating LA (as % of total fatty acids) was assessed in plasma cholesterol esters (CE) in the total cohort and in plasma phospholipids (PL) in a random subset of 833 patients. LA intake was assessed by a 203-item validated food frequency questionnaire. Prevalence ratios of T2D and associations with metabolic parameters were estimated in plasma and dietary LA quintiles using multivariable generalized linear models adjusted for demographic, lifestyle and dietary factors.

Results:
Patients were on average 69 years old, 79% was male and 77% were overweight or obese. Most patients used statins (86%), antihypertensive drugs (90%) and antiplatelet drugs (84%). A total of 813 patients (20%) had T2D. Mean LA intake (±SD) was 5.7±2.2 energy%, and circulating LA was 49.9±5.0% in CE and 18.7±3.0% in PL. Spearman’s correlations of dietary LA with circulating LA in CE and PL were 0.16 and 0.10, respectively. Higher plasma LA, but not dietary LA, was significantly associated with a lower diabetes prevalence (Table 1). BMI (β= -0.07, p<0.001), log non-fasting triglycerides (β= -0.01, p<0.001), log non-fasting glucose (β= -0.01, p<0.001), and log alcohol intake (β= -0.03, p<0.001) were significantly associated with circulating LA in plasma CE. Similar associations were found for LA in plasma PL. Dietary LA was not significantly associated with T2D prevalence and metabolic parameters (all p>0.05).

Conclusions:
Circulating LA may reflect both LA intake and metabolic state in drug-treated post-MI patients. This bears restrictions for its use as a biomarker of dietary LA intake in epidemiological studies.
Abstract P233: Changes in Diet, Lifestyle Behaviors, and Body Weight Over Two Years in Mexican Women
Authors: Tamez Martha , Mattei Josiemer , Monge Adriana , López-Ridaura Ruy , Lajous Martin
Published: July 2021

Background:
Some prospective observational studies have evaluated baseline diet and lifestyle behaviors, rather than changes in diet and lifestyle in relation to weight gain. Evaluating changes in diet and lifestyle on changes in adiposity may more appropriately identify effective strategies aimed at preventing weight gain.

Methods:
In a prospective cohort of Mexican female teachers (n=11,296) aged 35-65 y, we evaluated how two-year changes in diet and lifestyle behaviors relate to body weight change. We excluded women who were pregnant or who had prevalent heart disease, diabetes, or cancer at baseline, and those with implausible energy intake or missing baseline dietary, lifestyle, or weight data. We collected information on habitual consumption of foods and beverages with a validated food frequency questionnaire. Weight was self-reported and previously validated. We obtained data on physical activity, smoking, alcohol use, and TV watching through a self-administered questionnaire. We calculated the change in weight and diet/lifestyle behaviors by subtracting the information obtained in 2008 from that in 2006. We used multivariable linear regression models adjusting for age, state of residence, menopausal status, hormone replacement therapy, and all diet and lifestyle behaviors, simultaneously.

Results:
Increasing weekly servings of individual food components was positively associated with two-year body weight for intake of potatoes (0.06 kg; 95%CI 0.006, 0.12), corn (0.22 kg; 95%CI 0.006, 0.43), corn tortilla (0.03 kg; 95%CI 0.02, 0.04), sweets and desserts (0.01 kg; 95%CI 0.001, 0.03), Mexican dishes (0.13 kg; 95%CI 0.08, 0.17), and sodas (0.07 kg; 95%CI 0.05, 0.10). We observed an inverse association for intake of fruits (-0.006 kg; 95%CI -0.011, -0.001), vegetables (-0.013 kg; 95%CI -0.019, -0.008), and whole grains (-0.025 kg; 95%CI -0.045, -0.005). Lifestyle behaviors were also independently associated with weight change, including smoking (ever smokers=0.22 kg, starters=-0.24 kg, quitters=0.18 kg; p=0.04), physical activity level (decrease in category=0.14 kg, increase in category=-0.04 kg p=0.03), and TV watching (0.04 kg per hour/d; p=0.04). Changes in consumption of nuts, refined grains, low-fat and whole-fat dairy products, red and processed meats, beans, rice, diet sodas, and alcohol use were not associated with two-year weight change.

Conclusions:
Two-year changes in specific dietary and lifestyle behaviors were associated with modest changes in body weight. These results may be useful for targeted weight management messages.
Abstract P237: Moderate and Heavy Alcohol Consumption Are Associated With Decreased Systolic Function After 8 Years of Follow-up
Authors: Van Ballegooijen Hanne , Elders Petra J , Stehouwer Coen D , Dekker Jacqueline M , Beulens Joline
Published: July 2021

Introduction:
Excessive alcohol consumption is an important risk factors for cardiovascular disease, however, the underlying mechanisms are not well understood.

Hypothesis:
We assessed the hypothesis whether alcohol consumption is prospectively associated with unfavorable measures of cardiac structure and function.

Methods:
We used data from the Hoorn Study, a population-based, prospective cohort study. Data on self-reported alcohol consumption were collected with a validated food frequency questionnaire in 2000/2001(baseline for the current analyses). Echocardiography was performed in 2000/2001 in 582 participants and in 2007/2009 in 339 participants. Participants were classified into 5 categories based on self-reported alcohol consumption (glasses per week): 0 (non-drinkers), 0- 3 (light-drinkers), ≥3-7 (light to moderate drinkers), ≥7-14 (moderate drinkers) and ≥14 (heavy drinkers). Light drinking was considered the reference group. We studied the association of alcohol consumption with echocardiographic measures after 8 years of follow-up using linear regression analyses, adjusting for potential confounders.

Results:
The mean age was 69.8±6.5 years and 50% was female. After 7.4±0.5 years follow-up, moderate and heavy alcohol consumption were associated with a decreased left ventricular ejection fraction of -5.1% (-8.7, -1.4) for moderate and -4.8% (-8.8, -0.8) for heavy drinkers (Table). Heavy drinking was also associated with a decrease in left atrial volume index: -3.9mL/m
2
(-7.6, -0.2). No longitudinal associations were found between alcohol consumption and left ventricular mass index.

Conclusion:
Both moderate and heavy drinking were associated with decreased systolic function after 8 years follow-up. The toxic effect of alcohol could lead to underfilling of the left atrium which could lead to lower systolic function. These findings may explain the increased cardiovascular risk among people with excessive alcohol use.
Abstract P273: Treatment Patterns Among Vorapaxar New Users in a US Outpatient Clinical Setting
Authors: Pinto Cathy Anne , Fonseca Eileen , Hess Gregory P. , Manzi Massimiliano Alfonzo , Acquavella John
Published: July 2021

Introduction:
Vorapaxar is a once daily oral protease-activated receptor-1 (PAR-1) antagonist for the reduction of thrombotic events in patients with a history of myocardial infarction or peripheral arterial disease. Efficacy and safety was evaluated in a large randomized clinical trial (TRA 2°P TIMI 50), with a median follow-up of 30 months. This is the first descriptive study of vorapaxar treatment patterns in routine clinical practice.

Objectives:
To evaluate medication adherence and persistence among vorapaxar new users.

Methods:
Vorapaxar new users ≥18 years of age were identified with an index prescription date between June 2014 and October 2015 with ≥1 years of follow-up through October 2016. The qualifying prescription was identified from Symphony Health’s US outpatient pharmacy claims linked to private practitioner claims and hospital data. Baseline characteristics were assessed using a 1-year look-back prior to the index prescription date. Adherence was defined as a medication possession ratio (MPR) ≥80%, and persistence was defined allowing for up to a 7-day gap in days supply. Sensitivity analysis with 15-day gap to define persistence was performed.

Results:
The 529 vorapaxar new users included in the analysis were predominantly male (67%), 11% African American and 70% Caucasian, and had a mean (SD) age of 65.2 (10.5) years. At the end of 3, 6, and 12 months, 61%, 45%, and 32%, respectively, of new users were adherent on vorapaxar. A majority (68%) of vorapaxar users were persistent at 3 months, 48% at 6 months, and 29% at 12 months. An additional 10% restarted therapy by the end of the first year after a period of supply interruption. Results of the sensitivity analysis for persistence using 15-day allowable gap were within 1-2% of primary analysis. The median (IQR) time to discontinuation of therapy during the first year was 2.6 (1.2-6.1) months. During the first year, a median (IQR) of 5 (3-9) prescriptions per patient were filled- majority 30 day fills.

Conclusions:
Medication adherence and persistence of use decreased over time. One-third of patients were adherent and/or persistent at one year. Further research is warranted to understand treatment pattern differences by indication of use and factors affecting adherence and discontinuation.
Abstract P275: Prescription of PCSK9 Inhibitors in the United States, by Patient, Provider, and Payer Characteristics, 2016
Authors: Ritchey Matthew , Tsipas Stavros , Thompson-Paul Angela , Kirley Kate , Loustalot Fleetwood , Wozniak Gregory
Published: July 2021

Background:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved in 2015 for use by adults with familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease (ASCVD) requiring additional low-density lipoprotein cholesterol lowering beyond use of diet modification and maximally tolerated statin therapy. This study describes the patient, provider and payer related characteristics of prescriptions filled for this new class of injectable medication during 2016.

Methods:
2016 quarterly state-level prescription data were obtained from Symphony Health Solution’s PHAST 2.0. PHAST 2.0 includes data on over 90% of prescriptions filled from US retail and mail order pharmacies and, along with market purchasing data, are used to calculate state and national estimates. PCSK9 inhibitor fills among adults aged ≥18 years were characterized by quarter, patient age, provider type, and payer type. Per-capita fill rates across US states and total and patient spending per 30-day supply were calculated.

Results:
In 2016, 216,082 PCSK9 inhibitor prescriptions were filled. The number of fills per quarter increased from 20,348, in Q1, to 83,812, in Q4, and fill totals were greatest among those aged 65-74 years (39.3% of fills) (Figure). Cardiologists prescribed the majority of fills (60.5%). Commercial payers (43.3%) and Medicare (43.1%) were the most frequent payers. State per-capita fill rates (per 100,000) ranged from 12.1, in WY, to 191.9, in LA (median: 69.1). Total spending per 30-day supply was $951; patient spending was $58 per 30-day supply.

Conclusion:
Quarterly fills for PCSK9 inhibitors quadrupled during 2016, with substantial variation in per-capita fill rates across states. Cardiologists prescribed the majority of fills, which aligns with their indicated use among adults with FH or ASCVD. Total spending per 30-day supply was considerable. Tracking of prescribing trends for these medications is warranted as additional information about their efficacy becomes available.
Abstract P376: Improving Cardiovascular Health Among African-Americans Through a Community-based Mobile Health Lifestyle Intervention: The FAITH! (Fostering African-American Improvement in Total Health) App! Pilot Study
Authors: Brewer LaPrincess C , Jenkins Sarah , Lackore Kandace , Johnson Jacqueline , Jones Clarence , Cooper Lisa A , Radecki Breitkopf Carmen , Hayes Sharonne N , Patten Christi
Published: July 2021

Introduction:
Compared to Whites, African-Americans (AAs) have 82% lower odds of meeting ideal levels for five or more cardiovascular (CV) health components that comprise the American Heart Association’s Life’s Simple 7, an evidenced-based metric of seven health promoting behaviors and biological factors that improve CV outcomes. Given expanding mobile technology use among AAs, mobile health (mHealth) interventions are promising avenues to promote CV health within this population.

Hypothesis:
An evidence-based, theory-informed, culturally relevant, community-based mHealth lifestyle intervention would improve CV health among AAs adults.

Methods:
Five predominately AA churches collaborated in a community-based participatory research approach to develop a 10-week CV health and wellness digital application-based program (
FAITH! App
). We enrolled AA adults [N=50, mean age 49.6 (SD 12.7), 70% women (35/50)] into a single group, 10-week intervention centered on the
FAITH! App
with adjunct in-person sessions. The
FAITH! App
included ten core video education modules from health professionals on CV health, interactive diet/physical activity self-monitoring and a sharing board. The primary outcome was change in individual CV health behaviors (body mass index, physical activity, diet, cigarette smoking) and biological factors (blood pressure (BP), total cholesterol, fasting glucose) from baseline to post-intervention at 28 weeks.

Results:
Participants were overall high CV risk at baseline (hypertensive [40% (20/50)] with poor/intermediate physical activity [79% (37/47)] and diet [72% (36/50)]). At 28 weeks, there were substantial improvements in CV health factors (systolic and diastolic BPs), CV health behaviors (diet, physical activity) and psychological/psychosocial variables to promote behavior change (
Table 1
).

Conclusions:
This study supports the benefits of a culturally relevant, community-based mHealth lifestyle intervention to promote CV health among AAs with high cardiometabolic risk.
Abstract 17010: Metabolic Gene Expression and Mitochondrial Function Are Altered in the Failing Single Ventricle Myocardium
Authors: Garcia Anastacia M , Chatfield Kathryn C , Sparagna Genevieve C , Phillips Elisabeth K , Karimpour-Fard Anis , Stauffer Brian L , Sucharov Carmen C , Miyamoto Shelley D
Published: July 2021

Introduction:
Despite current standard of care, heart failure (HF) remains a leading cause of death and indication for transplant in the single ventricle congenital heart disease (SV) population. However, little is known regarding the molecular mechanisms underlying remodeling and eventual HF in SV patients. The purpose of this study was to characterize the transcriptional profile of SV myocardium in both failing (SVHF) and non-failing (SVNF) SV patients compared to biventricular NF controls (BVNF). Furthermore, we conducted high resolution respirometry to assess mitochondrial function in each of these populations.

Methods:
Library prep was performed using the TruSeq Ribo Zero rRNA depletion kit, and 2x150 total RNAseq (Illumina HiSEQ 4000) was performed on age-matched explanted RV myocardium from BVNF (n=4 biventricular donors), SVNF (n=8 SV primary transplants, normal function), and SVHF (n=9 SV systolic HF transplants). Samples were aligned to hg19 and were normalized and annotated using the edgeR pipeline. Significant changes in gene expression were calculated using an FDR adjusted p-value (q<0.1; p<0.025). Respiration of myocardial mitochondria was measured using a stepwise protocol to evaluate respiratory capacity in an Oroboros Oxygraph system; n=6 SVHF, n=6 SVNF, n=18 BVNF.

Results:
RNAseq identified 1,007 differentially expressed genes in SVNF and 2,109 in SVHF myocardium relative to BVNF controls. Transcriptome pathway analysis demonstrated multiple pathways that are similarly dysregulated in SVNF and SVHF, while pathways involved in mitochondrial metabolism and function were significantly dysregulated specifically in the SVHF population. Moreover, mitochondrial oxygen flux was significantly decreased, particularly through complexes I and II, in SVHF relative to BVNF controls.

Conclusions:
Our results provide new insights into SVHF by identifying unique gene expression changes, including those related to metabolism, and impaired mitochondrial function. Together these data suggest dysregulated metabolic gene expression and mitochondrial dysfunction are phenotypes associated with the failing single ventricle and may serve as potential therapeutic targets for the treatment or prevention of HF in the SV population.
Abstract 17024: Venous Thromboembolism (VTE) Mortality Trends in the Pediatric Population: A Retrospective Analysis of the National Inpatient Sample (NIS) Database
Authors: Salazar Adum Juan P , Golemi Iva , Tafur Alfonso J
Published: July 2021

Background:
Venous thromboembolism (VTE) is one of the leading preventable cardiovascular diseases and responsible for approximately 300,000 deaths per year in the US. There is paucity of data regarding mortality secondary to VTE in the pediatric population.

Aim:
To determine the mortality trends due to VTE in hospitalized patients among the pediatric population.

Methods:
We perform a retrospective analysis of the National Inpatient Sample (NIS) database. The cohort group consisted in hospitalized patients under the age of 18 with a diagnosis of VTE. We used the ICD-9 coding system to identify the diagnosis of VTE. Patients were included only if VTE was considered within the first four discharge diagnoses. We used simple logistic regression to calculate trends. All statistical analyses were performed in SPSS software version 22. Chicago, Illinois.

Results:
A total of 4961 (not weighted) patients (female: 2567 (51.7%), mean age: 12.19 (SD=5.7), neonate to infant: 553 (11.1%), toddler: 173 (3.5%), preschool: 197 (4%), school: 751 (15.1%), adolescent: 3287 (66.3%)) were included. The prevalence of VTE by age group showed a J-shaped curve and was more commonly seen among adolescents.
Fig. 1.
A total of 93 patients died (1.9%). Pulmonary embolism (PE) occurred in 1835 patients (36.5%). Among patients with PE, 4.4% died compared to 0.4% with non-PE (OR: 10.9 95% CI 5.8-18.1,
p:
<0.001). No trend in mortality was observed over a period of 10 years
p:
0.19.
Fig. 2.

Conclusion:
The inpatient mortality rate secondary to VTE among pediatric patients is low. Patients with PE have a 11-fold increased mortality likelihood compared to non-PE patients. No mortality trends were observed.
Abstract 17030: Multi-Center Prevalent and Incident Cohorts Replicate ST2 as a Biomarker of Disease Progression in PAH and is Associated With Right Heart Failure
Authors: Mazurek Jeremy A , Boxer Jeremy , McGlothlin Dana P , Forfia Paul R , Wu Alan H , De Marco Teresa , Rame J E
Published: July 2021

Introduction:
Pulmonary arterial hypertension (PAH) is defined by elevation in PA pressure (PAP) and pulmonary vascular resistance (PVR) resulting in right ventricular (RV) failure and is associated with significant morbidity and mortality. Prior studies have evaluated invasive hemodynamic and biomarker parameters of PAH progression and prognostication, including the prognostic role of ST2, a member of the IL-1 receptor family, which is upregulated in cardiopulmonary disease, including PAH.

Hypothesis:
Serum ST2 (sST2), is upregulated and prognostic of transplant free survival in PAH in 2 independent cohorts and is associated with parameters of RV function.

Methods:
The primary cohort comprised 191 largely prevalent PAH patients from the University of California San Francisco (UCSF) with 41 largely incident PAH patients from the University of Pennsylvania (Penn) in the validation cohort. The primary outcome was transplant free survival. The Presage high sensitivity ELISA was used to measure sST2.

Results:
The UCSF cohort was 72% female, mean age 50±15 years, 25% idiopathic & 25% connective tissue disease-PAH (CTD-PAH). Those with sST2 > median (32.5 (21.9, 53.0) U/ml) had decreased semi-quantitative RV function (p=0.0003) by echo and increased right atrial pressure ([RAP]; 11.5 vs. 8.0 mmHg, p=0.003) and decreased cardiac index ([CI]; 2.23 vs. 2.45 L/min/m2, p=0.04), vs. sST2 ≤ median. Patients with sST2 ≤ median had significantly increased survival compared to those with sST2 > median (figure). The Penn cohort was 70% female, mean age 56±11 years, 54% idiopathic & 26% CTD-PAH. Median sT2 was 34 (21.7, 45.5) U/ml with those > median having significantly increased RAP (10.5 vs. 6.2 mmHg), mean PAP (53.3 vs. 39.8 mmHg) and PVR (12.7 vs. 6.0 WU), and lower CI (2.21 vs. 3.05 L/min/m2) (all p-values<0.05). Transplant free survival was significantly higher in those with sST2 ≤ median vs. > median (figure).

Conclusions:
In 2 independent PAH cohorts, sST2 is predictive of survival and serves as a marker of invasive parameters of RV failure. That sST2 is associated with differences in mean PAP and PVR in the largely incident Penn cohort, as compared to the prevalent UCSF cohort, warrants further study, as does the mechanism behind the robust association of ST2 and PAH.
Abstract 17034: Diagnostic Accuracy of Diastolic Pressure Ratio Using a Microcatheter: An Analysis of the ACIST-FFR Study
Authors: Price Matthew , Yang Jaden , Chambers Jeffrey , Seto Arnold , Sarembock Iam , Raveendran Ganesh , Desai Manisha , Jeremias Allen , Matsumura Mitsuaki , Fearon William F
Published: July 2021

Background:
The diastolic pressure ratio (dPR) is a non-hyperemic index used to measure the ratio of distal coronary to aortic pressure during a diastolic portion of the cardiac cycle. dPR indices measured by a pressure wire have similar diagnostic accuracy as iFR for FFR. The accuracy of dPR using a microcatheter (MC) has not been defined.

Methods:
The ACIST-FFR study was a prospective, multicenter study of a pressure-monitoring MC in patients with stable CAD. Using an automated software algorithm, dPR with the MC was defined as the Pd/Pa at the location within the diastolic period that was 50% of the distance from the peak of one waveform to the peak of the next waveform, averaged over a 5-beat period. iFR with the MC was computed in the usual fashion by the core laboratory from the original pressure tracings.

Results:
A total of 161 paired data samples from 11 sites were analyzed. dPR was highly correlated with iFR (R
2
=0.992, AUC=0.998 with a mean bias of -0.0237 (95% CI, -0.0041 to -0.0011) and provided a sensitivity of 98%, specificity 96%, and diagnostic accuracy of 96.9%. The optimal cutpoint of dPR for FFR was 0.91 (AUC=0.886), which provided a sensitivity of 82%, specificity of 80%, and diagnostic accuracy of 81%. The diagnostic accuracy of iFR for FFR was 81%, with a sensitivity of 82%, and specificity 80%.

Conclusions:
With a MC system, a non-hyperemic diastolic pressure ratio is highly correlated with iFR, and provides similar diagnostic accuracy as iFR for FFR.
Abstract 17056: High-Throughput Physiological Assay for Force and Stiffness Quantification in IPS Derived Cardiomyocytes
Authors: Serrano Ricardo , McKeithan Wesley L , Mercola Mark , del Álamo Juan C
Published: July 2021

Introduction:
Cardiovascular disease persists as one of the leading causes of death in the U.S. Physiological assays with iPSC-cardiomyocytes have been quickly adopted for cardiac drug discovery, and the study of cardiac disease in vitro. Whereas most of these assays focus on the kinematics of voltage and calcium, assays that quantify contraction forces are less common. Moreover, there is no current high-throughput method to characterize the passive elastic properties of cardyomyocytes that contribute to dyastolic function.

Methods and Results:
We have developed a method to measure and characterize force of contraction and stiffness of beating cardiomyocytes, solely based on optical measurements. First, we created a device consisting of 96 well plates with soft deformable polyacrylamide gels, doped with fluorescent beads (A). IPSc cardiomyocytes are seeded on the gels and stained with Wheat Germ Agluttining (WGA). We then acquire videos of both membrane and beads (B). Our algorithm processes the videos with Particle Image Velocimetry to obtain instantaneous deformation fields on the cells (C) and the gel. Next, the traction stresses at the cell-substrate interface (D) are computed using Traction Force Microscopy, and the intracellular monolayer stress using Monolayer Stress Microscopy. Our algorithm computes temporal traces of strain on the cells (E), traction forces on the gel (F), and retrieve relevant parameters that characterize the signal (G). The elastic modulus of the cells is inferred by fitting the relationship between the measured intracellular stress and strain maps. We have validated our analysis by performing dose response curves on cardiomyocytes treated with isoproterenol, mavacamten, and omecamtiv mecarbil (H).

Conclusions:
To our knowledge, we present the first method that measures force and elasticity of cardiomyocytes in a high-throughput set-up, as well as a novel device that allows for the execution of such experiments.
Abstract 17058: Generalizability of Outcomes From Cardiac Resynchronization Therapy Trials to African-Americans
Authors: Essilfie Gilbert , Franklin Sona , Ahiable Lilian E , Fontaine John M
Published: July 2021

Generalizability of Outcomes from Cardiac Resynchronization Therapy Trials to African-Americans

Introduction:
Underrepresentation of African-Americans in clinical trials calls to question the generalizability of the observed results to this population.

Methods:
We studied 294 Caucasians and African-Americans and compared outcomes with those reported in major cardiac resynchronization therapy trials (CRT). Results from MIRACLE, COMPANION, CARE-HF, REVERSE, and MADIT-CRT were analyzed. Kaplan-Meier survival analysis and Cox proportional hazards regression were applied to our dataset.

Results:
We included 294 patients (45% African-Americans). In African-Americans the mean age was 65±12 compared with 70±13 for Caucasians, (p=0.0003). The median follow-up was 8.1± 6 years. Baseline characteristics were similar to landmark trials in age, ejection fraction, proportion with ischemic cardiomyopathy (ICM), diabetes mellitus and glomerular filtration rate (GFR). African-Americans had similar NYHA functional class as in MIRACLE, COMPANION, and CARE-HF. Survival in our patients was 7.6±0.3 years (95% CI 6.9-8.2). There was no difference in mortality between African-Americans (28%,) and Caucasians (37%, P=0.19) compared with that reported in MADIT-CRT (29 and 22%, respectively). Treatment with an aldosterone antagonist and a GFR greater than 60 were associated with lower mortality (P=0.04 and P=0.005, respectively). In African-Americans lack of treatment with an angiotensin converting-enzyme inhibitor (ACEI), GFR less than 60, and ischemic cardiomyopathy (ICM) were associated with increased mortality when compared with Caucasians (P=0.01, P=0.03, and P=0.04, respectively). In Caucasians, none of these variables were associated with increased mortality.

Conclusions:
Despite lack of specificity in details from the major trials, African-Americans had similar mortality outcomes as reported in the initial trials. These results support extrapolations of outcomes from landmark trials to African-Americans.
Abstract 17059: Re-Use of Clinical Trial Data From the NHLBI Data Repository (BioLINCC) for Patient-Level Meta-Analyses of Cardiovascular Outcomes: Challenges and Opportunities
Authors: Sviglin Helena , Dandi Gauri , Navarro Almario Eileen , Patel Tejas , Wu Colin O , Tian Xin , Csako Gyorgy , Shamsuzzaman Md , Tesfaldet Bereket , Fleg Jerome , Kettermann Anna , Gandotra Charu , Sopko George , Cooper Lawton , Coady Sean , Banerjee Avantika , Farooque Nashwan , Hoque Laboni , Cure Carlos , Kirby Ruth , Liu Lijuan , Chen Jue , Yan Ye , Chowdhury Iffat , Burkhart Keith , Calis Karim , Leifer Eric , Szarfman Ana , Domanski Michael , Pucino Frank , Rosenberg Yves , Hasan Ahmed A
Published: July 2021

Introduction:
An objective of the Meta-AnalyTical Interagency Group (MATIG) is to conduct patient-level meta-analyses of cardiovascular outcomes using data from publicly available repositories. We describe challenges with data re-use from a seminal trial, provide a systematic approach to identify and curate data elements for hypothesis generation, and establish stackable trials to support these analyses.

Methods:
We used data from the ACCORD trial to assess risk factors and their gender specific differences for the event of hospitalization or death due to heart failure (hdHF), in patients with type 2 diabetes*. We identified the data elements needed to answer the research questions, reviewed the trial protocol to verify definitions, extracted patient-level data, performed quality assessment and statistical analysis. The results showed a gender difference in the effect of intensive vs. standard glucose-lowering therapy on hdHF. To validate the findings, we sought additional trials in BioLINCC to develop a compendium for meta-analysis, and repeated these steps for each trial.

Results:
Challenges for reusing the ACCORD trial included access to complete patient-level data and metadata. The compendium, developed to evaluate the stackability** of data across trials, identified differences in trial designs, patient populations, study interventions, and data elements that may impact the feasibility and interpretation of meta-analysis. An example of compendium components is shown in Table 1.

Conclusion:
High-quality metadata facilitate re-use of trial repository data. This compendium standardizes common data elements for gender, racial and age-group specific outcome assessment in major clinical trials. It provides the framework to assess the fitness of trials for patient-level meta-analyses. Efforts are underway by MATIG to expand the compendium to include risk factors and major cardiovascular outcomes across multiple large trials for meta-analysis.
Abstract 17065: Final Results of the AHA Guideline Transformation Optimization Initiative
Authors: Sasson Comilla ,   GTO Advisory Group, Jacobs Alice
Published: July 2021

Background:
Although guideline directed care has been shown to improve outcomes of Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) patients, dissemination and implementation of updated guideline recommendations are variable and often delayed.

Methods:
In 2014, the American Heart Association (AHA) launched the Guideline Transformation Optimization (GTO) initiative, designed to decrease the time to implementation of guideline recommendations by increasing knowledge and awareness for three target audiences: healthcare professionals, patients, and hospital systems. Guideline content was delivered using rapid formats via mobile applications intended for point-of-care provider and patient use, web-based content and media campaigns. The first guidelines to undergo this new organizational paradigm shift were the 2014 NSTE-ACS Guidelines and the 2016 Dual Antiplatelet Therapy Focused Update. We determined the reach to our target audiences and hospital-level achievement of NSTE-ACS quality measures using 2016 data from ACTION Registry-Get-With-The Guidelines.

Results:
Over 3 years (2014-17), there were 83,000 downloads of the healthcare professional mobile application and 4,365 attendees at 4 AHA professional education webinars. As a result of attending the webinar, 87% of learners said their practice would change. The patient campaign achieved over 2.7 billion media impressions, 32.6 million unique visitors to AHA’s heart attack webpages, and 26.2 million social media engagements. My Cardiac Coach mobile application for NSTE-ACS was downloaded by 8,500 patients. Among the 797 participating AHA “Mission: Lifeline” hospitals, 42 achieved early adopter recognition in 2015, defined as achieving all 5 target quality measures: cardiac rehabilitation referral, ACE/ ARB prescription at discharge, dual antiplatelet prescription, evaluation of left ventricular systolic function and smoking cessation education. Recognition was achieved by 296 hospitals in 2017.

Conclusion:
Three years after launch of the GTO initiative, AHA was able to meet its 2020 goals of decreasing time to translation of scientific guidelines, increasing provider and patient education and awareness, and increasing guideline adherence in almost 300 U.S. hospitals.
Abstract 17091: High Efficient Therapeutic Genome Editing in Cardiovascular Endotheliumby Nanoparticle Delivery of Crispr Plasmid
Authors: Jin Hua , Huang Xiaojia , Zhang Xianming , Zhao Youyang
Published: July 2021

Introduction:
Therapeutic delivery of CRISPR system components to induce
in vivo
genome editing in postnatal life has great translational potential. Recent studies employing non-viral delivery of small guide RNA (gRNA) and Cas9 mRNA have achieved efficient
in vivo
genome editing in adult mice. However, as often seen in other RNA therapeutic studies with non-viral delivery of antisense and siRNA, the efficiency is limited to the liver.

Hypothesis:
Novel nanoparticle can deliver CRISPR system components in vivo to selectively target cardiovascular endothelium in adult mice.

Methods:
We developed a novel nanoparticles. Mixture of the nanoparticle:plasmid DNA expressing Cas9 under the control of the human
CDH5
promoter and gRNA driven by the
U6
promoter was administered i.v. to adult mice. Seven to ten days later, various organ tissues were collected for analysis of the efficiency of genomic editing and knockout of protein expression. The phenotype of CRISPR-mediated in vivo knockout of
Pik3cg
which encodes the G protein-coupled receptor-activated p110gamma isoform of PI3K was compared to
Pik3cg
null mice in response to sepsis challenge.

Results:
Therapeutic delivery of nanoparticles loaded with the all-in-one CRISPR plasmid DNA induced highly efficient genome editing in endothelial cells (ECs) of the cardiovascular system including lung, heart, aorta, and peripheral blood vessels in adult mice. The Indel rate was as great as 50% in ECs isolated from these vascular beds. Immunostaining and Western blotting demonstrated greater than 70% decrease of protein expression in cardiovascular endothelial cells.
Pik3cg
-gRNA-induced genome editing diminished p110γPI3K expression in pulmonary vascular ECs, which led to impaired vascular repair and resolution of inflammation after sepsis challenge as seen in

Pik3cg
-/-

mice.

Conclusion:
We have developed a simple and highly efficient method for
in vivo
genome editing selectively in the cardiovascular endothelium. This strategy will greatly facilitate cardiovascular research and may enable therapeutic genome editing for prevention and treatment of cardiovascular diseases.
Abstract 17101: Targeting of Heparin-Binding EGF-Like Growth Factor (HB-EGF) Effectively Protected Against Hyperlipidemia-Associated Vascular and Hepatic Inflammations
Authors: Kim Seonwook , Yang Lihua , Temel Ryan E , Lee Richard G , Graham Mark J , Lee Sangderk
Published: July 2021

Introduction:
Obesity and hepatic VLDL overproduction are key risk factors for the development of dyslipidemia and metabolic inflammatory diseases including atherosclerosis and non-alcoholic fatty liver disease (NAFLD). HB-EGF is a representative mediator for sustained EGFR transactivation under diverse oxidative stress environments including central obesity. A previous report showed that, in C57BL/6 mice, an injection of recombinant HB-EGF significantly increased apoB and TG secretion from the liver; in contrast, HB-EGF antisense oligonucleotide (ASO) administration induced a significant suppression of the hepatic VLDL secretion.

Hypothesis:
In this study, we tested the hypothesis, which was, that HB-EGF is an autonomous stimulator for the hepatic VLDL production in the liver, which would result in the development of hypertriglyceridemia, causing metabolic inflammatory diseases when under obese and over-nutrition.

Methods and Results:
In liver-derived cell line HepG2, recombinant HB-EGF treatment induced an autonomous increase of apoB production in the cells. In LDLR deficient mice under a western diet, which showed a list of metabolic syndrome phenotypes, HB-EGF ASO administration induced an effective downregulation of circulatory VLDL and TG level. The HB-EGF ASO administration also showed effective protection against atherosclerosis and non-alcoholic steatohepatitis (NASH) phenotypes in the mouse model.

Conclusions:
The results suggest that HB-EGF is a positive stimulator of hepatic VLDL production that may cause hypertriglyceridemia under obese and over-nutrition. It was also demonstrated that HB-EGF targeting could be an effective approach to prevent and reverse vascular and hepatic inflammations as shown in a mouse model.

Figure:
LDLR deficient mice under western diet were treated with control and HB-EGF ASOs for 12 weeks. CD68 positive cell content and inflammatory gene MCP1 transcription level in liver were compared.
Abstract 17105: Is There a Difference in Lean and Fat Mass in HF Patients Based on NYHA Classifications (I-II versus III-IV)?
Authors: Haedtke Christine , Moser Debra K , Pressler Susan J , Lennie Terry
Published: July 2021

Introduction:
As NYHA Class increases from I (ordinary physical activity does not cause undue fatigue), to Class IV (Symptoms are present while at rest) physical limitations become severe. It has previously been shown that HF patients have increased fat within the muscle thus decreasing exercise performance and tolerance. It is unclear if all NYHA classes are similarly affected.

Hypothesis:
HF patients with NYHA class III-IV will have more fat and less lean mass than those with NYHA class I-II.

Methods:
Secondary data analysis using cross sectional data from N=253. The parent study was a multicenter study about nutrition and body composition among patients with HF (preserved or reduced, and NYHA classification I-IV) who had been on a stable medication regimen, able to participate in dual-energy X-ray absorptiometry scan and/or BodPod body composition measures, able to read and speak English, and had no cognitive impairment. Women and men were analyzed separately due to known differences in fat and lean mass.

Results:
Table 1: Sample characteristic’s

Testing the hypothesis using 2-way ANOVA and comparing the percentage of body weight that is lean and fat mass in NYHA class I-II vs III-IV found the interaction of gender and NYHA was not significant in either % lean or %fat (p=0.221, 0.190 respectively). NYHA class by itself was not significant (p=0.067) in %lean but was significant in %fat (p=0.046). Gender was significant in both %lean and %fat with men having 9.6% less fat (1.139 SE) and 9.8% more lean mass (1.066 SE) (p≤0.001). NYHA class III-IV had 2.3% (1.139 SE) more fat than those in NYHA class I-II. The R squared was 0.265 and adjusted R squared was 0.256.

Conclusions:
Part of our hypothesis was correct in that NYHA class III-IV had more fat mass than those in class I-II, but no difference was found in lean. This is an unexpected finding as healthy people gain fat mass while losing lean mass as they age. Additional studies are needed to further examine this result.