bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10621: Prediction of Incident Atherosclerotic Cardiovascular Disease Using Traditional and Polygenic Risk Score Modeling: The Million Veteran Program Experience
Authors: Posner Daniel C , Vassy Jason L , Pencina Michael J , Assimes Themistocles L , Galloway Ashley , Ho Yuk-lam , Gagnon David R , Casas Juan P , Damrauer Scott M , Gaziano Michael , Cho Kelly , Wilson Peter W , Sun Yan V
Published: March 2022

The prediction of myocardial infarction (MI), acute ischemic stroke (AIS), cardiovascular (CVD) death, and 3-point MACE (MI, AIS, or CVD death) in Million Veteran Program (MVP) participants over 8 years of follow up was evaluated using environmental/traditional risk factors (“E”), polygenic risk scores (“G”), and a combination of both approaches (“GxE”). Individuals free of atherosclerotic cardiovascular disease (ASCVD) at baseline were included. Risk factor levels for the participants close to the time of MVP enrollment for age, sex, systolic blood pressure, cholesterol, HDL cholesterol, smoking status, and diabetes status were analyzed. Outcomes were determined from VA electronic record data, Medicare/Medicaid data, and the National Death Index. Analyses were undertaken separately for non-Hispanic European (EUR), African American (AFR), and Hispanic (HIS) participants. There were 157,941 veterans at risk with 8,157 MI events, 2,024 AIS events, 1,778 CVD deaths, and 9,350 3-pt MACE events over 8 years of follow-up. The overall results showed good performance with the environmental model for all three racial-ethnic groups, with C-statistics ranging from 0.69 to 0.77. The G models showed very modest prediction capabilities and similarly modest improvement in the combined GxE models. In conclusion, traditional risk factor modeling has been shown to be highly effective and, in the MVP experience, the additional impact of genetic or genetic interaction information was small.
Abstract 10622: Z Scores in Pediatric Cardiac Magnetic Resonance: Reclassification of Smaller, Younger Hearts with Novel Calculator
Authors: Gurijala Nyshidha , Loke Yue-hin , Cross Russell , Hamann Karin , Olivieri Laura
Published: March 2022

Introduction:
The use of z scores to describe growth of normal structures is necessary in the management of pediatric cardiac disorders, particularly in babies and toddlers. Z score calculators for cardiac magnetic resonance (CMR) have traditionally relied on a convenience sample given complexity of the test. A recently published, novel z score calculator from prospectively-imaged, awake, healthy children ages 0-12 years may add value to assessments of ventricular size compared to traditional calculators.

Hypothesis:
A novel z score calculator (“Olivieri et al”) with robust prediction in younger, smaller children may reclassify right and left ventricular end diastolic volumes and mass (RVEDV, LVEDV, LVM) compared to the traditional calculator (“Buechel et al”).

Methods:
A retrospective cohort of subjects less than 12 years of age who underwent clinical CMR imaging on a 1.5T scanner (n=96; median age 5.5 years (IQR 3.7-7.6 years); 42% female) was studied. Z scores were calculated using both novel and traditional models for RVEDV, LVEDV and LVM. Subjects were categorized into the agreement group (both calculators agree) or disagreement groups, where novel calculator reclassified to normal (z< ± 2) or abnormal (z> ±2). Reclassified subject characteristics were compared with ANOVA and t-test.

Results:
Novel and traditional z scores agreed for 77%, 58% and 62% of cases for RVEDV, LVEDV and LVM, respectively. Amongst disagreements, subjects reclassified from abnormal to normal by the novel calculator had significantly lower age, BSA and RV size (Table 1). Reclassified subjects showed no association with specific diagnoses.

Conclusion:
The novel z score calculator reclassifies younger, smaller children away from severe z scores into more normal z scores. Ventricular volume assessment is highly relevant to critical decision-making in the first years of life in borderline lesions.
Abstract 10625: A RE-AIM Evaluation of Lay Advisor Interventions to Improve Hypertension Outcomes - A Systematic Review
Authors: Patil Sonal , Bhayani Vishwa , Yoshida Yilin , Wilson Gwendolyn , Stange Kurt , Saper Robert
Published: March 2022

Context:
Lay advisor interventions improve hypertension outcomes, especially in vulnerable populations. However, the incremental benefit of adding these interventions, and factors that could inform their widespread implementation, are unknown.

Objective:
Inform real-world choices about implementation of lay advisor hypertension interventions.

Methods:
We systematically searched several databases, including Medline, CINAHL, SCOPUS, from January 1, 1980 to December 2020. We included all study designs of hypertension interventions delivered solely by a lay advisor. Search terms for lay advisors included peers, community health workers, barbers, and faith-based activists. Studies of lay advisor interventions combined with other health professional interventions were excluded. Two independent reviewers coded eligible articles using a validated data extraction tool based on the Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM) framework.

Results:
Of 5986 unique citations, 21 were eligible for inclusion. Most studies showed improvements in hypertension outcomes, but outcomes predominantly were measured shortly after intervention completion. Inclusion/exclusion criteria and lay advisor recruitment and training were usually well-described, and primary outcomes were reported. Participation rates were infrequently reported. None reported adverse outcomes. Only 14% (3 of 21) of studies reported qualitative assessments. External validity domains of adoption, implementation, and maintenance were rarely reported. In the adoption domain, no study reported comparisons of delivery and non-delivery settings or staff representativeness. Presence of previous lay advisor programs in the community improved adoption and implementation. One study mentioned costs of implementation for maintenance.

Conclusion:
Few studies have examined the incremental effectiveness of adding a lay advisor intervention for hypertension outcomes, most show improvement. Indicators of external validity of lay advisor interventions are not well-reported. Future research designs should improve reporting across RE-AIM dimensions, particularly indicators of external validity, including qualitative assessments.
Abstract 10628: The Role of Hepatic Endoplasmic Reticulum Homeostasis in Liver-Heart Crosstalk in Sepsis
Authors: Li Mark , Qian Qingwen , Zhang Zeyuan , Harata Mikako , Philibert Winter , Chen Biyi , Rauckhorst Adam , Taylor Eric B , Abel Dale , Song Long-sheng , Yang Ling
Published: March 2022

The heart demands continuous supply of energy substrates, primarily in the form of lipids, to sustain its contractility and other functions. During episodes of severe stress such as sepsis, an overwhelming pathogen-induced systemic immuno-metabolic response, the heart heavily relies on lipid particles synthesized at the endoplasmic reticulum in the liver. However, it is currently unknown how this lipid-dependent crosstalk supports cardiac function during stress and how it is regulated in the liver. In this study, we employed proteomic, lipidomic, and metabolomic approaches to show that hepatic Inositol-Requiring Enzyme 1 α (IRE1α), a key regulator of ER homeostasis, interacts with and regulates the activity of Fatty Acid Synthase (FAS), a well-known enzyme that synthesizes lipids. Notably, this dynamic physical interaction was disrupted in the setting of experimental sepsis induced by lipopolysaccharide (LPS). Specific deletion of IRE1α in the liver sensitized mice to LPS-associated mortality due to cardiac dysfunction. Mechanistically, we found that loss of IRE1 did not alter hepatic or systemic cytokine response, but suppressed FAS enzymatic activity, compromising the adaptive hepatic lipid metabolic reprogramming in response to the LPS challenge. Notably, IRE1α deletion diminished the LPS-induced lysophosphatidylcholine (LPC) secretion from the liver, a critical lipid species that is positively correlated with survival in septic human patients. In turn, this impaired hepatic ER-mediated lipid reprogramming contributed to cardiac dysfunction in part through reducing cardiac oxygen consumption and promoting neutrophil infiltration in response to sepsis. Together, our study provides the first insight into how adisruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance. Knowledge gained from this study might speed the development of novel therapeutic targets for hepatic ER homeostasis in sepsis-associated heart dysfunction.
Abstract 10631: Exosome-Encapsulated Adeno-Associated Viruses as a Novel Cardiotropic Vector for Gene Therapy in Heart Failure
Authors: La Salvia Sabrina , Li Xisheng , Liang Yaxuan , Adamiak Marta , Parikh Mihir , Okoli Kimberly , Gonzalez-Kozlova Edgar , Dogra Navneet , Dubois Nicole C , Hajjar Roger J , Sahoo Susmita
Published: March 2022

Adeno-associated viruses (AAVs) are the vectors of choice for long-term delivery of genes to the heart and due to their safety in clinics. Despite its many favorable features, a notable drawback is the presence of preexisting neutralizing antibodies (NAb), which bind to free AAVs and impair their clinical effect. Here, we describe delivery of AAVs encapsulated in extracellular vesicles (eAAV), as a superior cardiac gene delivery system that offers higher NAb resistance.

Methods:
Ultracentrifuge-isolated eAAVs were characterized using TEM, DLS, qNano, nanoflow cytometry, ExoView, qPCR and Western blot. Gene delivery efficacy of free AAV and eAAVs were compared with and without NAbs using human cardiomyocytes in vitro, and in mice in vivo, using flow cytometry (with mCherry) and bioluminescence imaging (with luciferase). Therapeutic efficacy of gene delivery by free AAV and eAAV in presence and absence of NAb was determined using a cardiac contractile gene SERCA2a in a mouse model of myocardial infarction (MI). eAAV uptake and trafficking was studied both in vitro and in vivo using fluorescence dye-labeled eAAV.

Results:
eAAV outperformed free AAV in delivering genes even in the presence of NAbs, both in vitro and in vivo. SERCA2a delivered by eAAV significantly improved cardiac function (ejection fraction, %EF, ~60%) compared to when delivered by free AAV (~40%) or saline control (~20%), in intramyocardially injected MI mice with NAb. Fluorescence-tagged eAAVs injected to mouse hearts were internalized into all cell types (CMs and non-CMs), but, eAAV-mCherry was primarily expressed in CMs, indicating that eAAV-mediated gene delivery is cardiotropic. eAAVs were uptaken in to acidic endosomal (Rab5 & 7 positive) compartments of cultured cardiomyocytes and delivered significantly higher amounts of luciferase to the nucleus of human CMs compared to free AAVs. This uptake of eAAVs was inhibited by the proton pump inhibitor in endosomes, Bafilomycin A1.

Conclusion:
Our study demonstrated that eAAV-mediated gene delivery can circumvent neutralizing antibody (NAb) issue for gene therapy. eAAVs are cardiotropic and deliver genes to the nucleus via uptake into acidic endosomes. eAAV is a superior gene delivery vector and a new platform to treat heart failure.
Abstract 10632: Variation in the Association Between Beta Blocker and/or Rasi Use After Discharge and Outcomes in Hfref by Age
Authors: Gilstrap Lauren , Skinner Jonathan , O'Malley James , Solomon Nicole , Chiswell Karen , Fonarow Gregg C , Bhatt Deepak L , Yancy Clyde W , Devore Adam D
Published: March 2022

Introduction:
Given the increasing age and comorbidity burden of HFrEF patients, there are questions regarding whether the net risk/benefit of guideline directed medical therapy (GDMT) varies across the age spectrum. The aim of this study was to use Get With The Guidelines-Heart Failure data linked with Medicare claims to determine whether the association between selected GDMT and outcomes in HFrEF varies across the age spectrum.

Methods:
We identified 48,711 eligible patients from 330 different centers admitted with HFrEF between 2008 and 2016 using GWTG-HF and Medicare. We created two cohorts: those prescribed evidence-based beta blockers (BB) and/or renin-angiotensin system inhibitors (RASI) and those prescribed neither. We used overlap weighting to match the patient populations within age strata (65-74, 75-84 and 85+). We then used Cox proportional hazard models to determine the association between use at discharge and 30-day and 1-year mortality and readmissions.

Results:
The average HFrEF patient in this dataset was 79 (95% CI 72, 85) years old and 41% were female. Eighty percent were white. Ninety-seven percent (=47,299) received BB and/or RASI; 3% (n-1,412) received neither. The hazard ratio (HR) for BB and/or RASI vs. no BB or RASI for 1-year mortality or readmission among those aged 65-74 was HR=0.82 (95% CI 0.70-0.95); for those aged 75-84 HR=0.86 (95% CI 0.78-0.95) and for those aged 85+, the HR=0.78 (95% CI 0.71, 0.86). The p-value comparing HR across the age strata was 0.41. Similar results were observed for 30-day outcomes
(Table 1)
.

Conclusions:
The association between use of BB and/or RASI at hospital discharge and lower 30-day and 1-year mortality or readmission does not appear to vary across the age spectrum. Absent a contraindication, BB and/or RASI should be prescribed for all patients at discharge regardless of age.
Abstract 10646: The Use of Beta Blockers and Renin Angiotensin System Inhibitors Among Patients with Concurrent HFrEF and Alzheimer’s Disease and Related Dementias (ADRD)
Authors: Gilstrap Lauren , Ouellete Greg , Cohen Andrew , Flint Danette , Gladders Barbara , Austin Andrea , Skinner Jonathan
Published: March 2022

Introduction:
Recent data suggests that patients with concurrent HFrEF and ADRD (HF+ADRD) have markedly higher mortality than HFrEF patients without ADRD. One of the proposed mechanisms for this is a lower rate of guideline directed medical therapy (GDMT) use in the HF+ADRD population. The aim of this study is to determine the change in GDMT use before and after HFrEF hospitalization for patients with HF+ADRD.

Methods:
We used 100% Medicare Parts A and B and a random 40% sample of Part D to create a cohort of 397,680 fee-for-service beneficiaries with ≥1 hospitalization for HFrEF between 2012 and 2018. We used previously validated ICD-9/10 codes to define ADRD. We created 4 exposure groups for both evidenced-based beta-blockers (BB) and renin angiotensin system inhibitors (RASI): “continued” (on drug before and after hospitalization); “initiated” (not on before, but on after); “discontinued” (on before, but not after) and “never started” (not on before or after).

Results:
Rates of BB continuation (42% vs. 37%, p<0.001) and initiation (24% vs. 18%, p<0.001) were higher among HFrEF patients without ADRD (
Table 1
). Rates of BB discontinuation (13% vs. 10%, p<0.001) and never starting (32% vs. 24%, p<0.001) were higher among HF+ADRD patients. Similarly, rates of RASI continuation (33% vs. 26%, p<0.001) and initiation (18% vs. 15%, p<0.001) were higher among HFrEF patients without ADRD. Rates of RASI discontinuation (15% vs. 14%, p<0.001) and never starting (44% vs. 35%, p<0.001) were higher among HF+ADRD patients.

Conclusions:
Rates of BB/RASI continuation and initiation are higher among HFrEF patients without ADRD while rates of BB/RASI discontinuation and never starting are higher among HF+ADRD patients. Additional work is needed to understand why GDMT use is lower in patients with HF+ADRD and to determine whether, in this population, there are adverse outcomes associated with failing to receive GDMT, such as increased HFrEF symptoms, hospital admissions, and mortality.
Abstract 10647: Accreditation Identifies Operator Variability and Gaps
Authors: Weiner Bonnie H , Cigarroa Joaquin E , Cowley Michael J , Marshall J J
Published: March 2022

Background:
Accreditation (A) is an ongoing process to assist facilities in achieving and maintaining quality in the catheterization laboratory. Independent review of randomly selected cases can provide insight into changes that occur over time. The current analysis assesses the differences between new operators (NO) and those previously reviewed (PO) over a series of reviews at 2 year intervals.

Methods:
Randomly selected cases from each site and at each timepoint are reviewed by blinded, independent interventional cardiologists and all data are recorded on a standard case report form. After the review was completed, each operator was identified as NO or PO. Statistical analysis was performed using JMP pro (version 15.2.1, SAS Institute Cary NC).

Results:
17 facilities underwent initial and as many as 3 reaccreditation visits. A total of 2702 cases were reviewed and this analysis was limited to the 1550 PCI (608 Initial, 663 RA1, 224 RA2, 35 RA3). Selected variables are shown in Table 1. Although many findings are not different between NO and PO, those differences identified are primarily those related to documentation.

Conclusions:
We have previously identified changes over time from a facility standpoint where after initial improvement, there is a loss of improvement. Similar findings are identified when NO are compared to PO but documentation differences are identified. Locum Tenens physicians are increasing used for coverage. Adequate onboarding is critical to maintaining a quality culture and continued reinforcement will assist existing operators.

Table
Abstract 10648: The Presence of Iatrogenic Atrial Septal Defect Does Not Affect the Right Ventricular Strain Function in Patients with More Than Moderate Tricuspid Regurgitation
Authors: Chao Chiehju , Seri Amith , Fennellly Evelyn , Campany Megan , Kenyon Courtney , Fath Ayman , Smith Sean , Buckner-Petty Skye , Rayfield Corbin , Fortuin David , Sweeney John , Mackram Eleid , Alkhouli Mohamad , RIHAL Charanjit S , Pollak Peter , El Sabbagh Abdallah , Arsanjani Reza
Published: March 2022

Background/Introduction:
More than moderate tricuspid regurgitation (TR) at baseline is associated with worse outcome in MitraClip patients. The presence of iatrogenic ASD (iASD) may cause right-sided volume overload and lead to adverse events. However, the real effects of iASD are not well-investigated in these patients who are vulnerable to right-sided volume overload.

Methods:
Patients with more than moderate TR who underwent a successful MitraClip procedure in the period from June 2014 to September 2020 were identified from the Mayo institutional NCDR database. Follow-up transthoracic echocardiography (TTE) at about 1 year after the procedure was used to determine the presence of iASD, and speckle-tracking strain analysis was done. Patients were grouped according to the presence of iASD (iASD+ group vs. iASD- group) for statistical analysis.

Results:
A total of 141 consecutive patients were included for the final analysis (iASD+ group n=44 and iASD- group n=97). The mean age was 79.3 ± 8.8 years, and 72.3% were male. Follow-up echocardiography and speckle-tracking strain data did not show a significant difference in either left or right ventricular function in conventional echocardiographic parameters and strain. LA reservoir strain (13.7 ± 6.9 vs 11.5±7.5, P=0.0418) was the only parameter with significant difference among the two groups. Details are summarized in
Table 1
.

Conclusion:
The presence of iASD can decompress the left atrium, but does not affect left or right ventricular strain function in MitraClip patients with more than moderate baseline TR.
Abstract 10649: Changes Over Time in Hemoglobin A1c (hba
1c
) Levels Predict Long-Term Survival Following Acute Myocardial Infarction
Authors: Shiyovich Arthur , Gilutz Harel , Plakht Ygal
Published: March 2022

Introduction:
Frequent fluctuations in hemoglobin A1c (HbA
1C
) values are independent predictors of diabetic complications and patient outcomes.

Objective:
To evaluate the prognostic significance of HbA
1C
levels and its changes among diabetic patients after non-fatal AMI.

Methods:
Patients with diabetes mellitus (DM) who were admitted to a tertiary medical center with AMI throughout 2002-2017 and survived >1year thereafter were evaluated. All the results of HbA
1C
values during the follow-up period (up to 10-years after discharge) were obtained and analyzed. The changes (Δ) of HbA
1C
were calculated for all pairs of tests in each patient. The time interval of ΔHbA
1C
values was classified as rapid (<1 year) and slow (≥1 year) change. The outcome was all-cause mortality.

Results:
A total of 4,066 patients were analyzed, mean age 66.4±11.9 years, 36% females. A U-shaped association was observed between HbA1C and mortality: adjOR=1.887 and adjOR=1.302 for HbA
1C
<5.5% and ≥8.0% respectively, as compared with 5.5-6.5% (p<0.001). A U-shaped independent association between ΔHbA
1C
and long-term survival was found: adjOR=2.376 and adjOR=1.340 for the groups of <-2.5% and ≥2.5% HbA
1C
changes respectively (p<0.001 for each), as compared to the group of minimal ΔHbA
1C
(±0.5%). Rapid increase in HbA
1C
(but not decrease) following AMI was associated with greater risk for mortality.

Conclusions:
HbA
1C
values, its changes and their rate are significant independent prognostic markers for long-term all-cause mortality with a U-shaped association following non-fatal AMI among DM patients. Thus, ΔHbA
1C
and its timing, in addition to absolute HbA
1C
values should be monitored among these patients.
Abstract 10654: Prevalence and Outcomes of Patients with HFrEF and Alzheimer's Disease and Related Dementias (ADRD)
Authors: Gilstrap Lauren , Ouellet Gregory , Cohen Andrew , Flint Danette , Gladders Barbara , Austin Andrea , Skinner Jonathan
Published: March 2022

Introduction:
The average Medicare beneficiary with HFrEF is now 80 years old. Alzheimer’s Disease and Related Dementias (ADRD) is more common among older adults. Yet, to date the rate of ADRD in HFrEF has not been well studied. This is important because the treatment of HFrEF relies on a complex medication regimen and often-challenging lifestyle modifications, things that are particularly difficult in the setting of concurrent cognitive impairment. The aim of this study is to determine the prevalence and outcomes of patients with concurrent HFrEF and ADRD (HF+ADRD).

Methods:
We used 100% Medicare Parts A and B and a random 40% sample of Part D to create a cohort of 397,680 fee-for-service beneficiaries with ≥1 hospitalization for HFrEF between 2012 and 2018. We required 1 year of FFS before and after discharge to capture comorbidities and measure outcomes over time. We used previously validated ICD-9/10 codes to define ADRD.

Results:
Thirteen percent (n=53,092) of patients with HFrEF have concurrent ADRD. The average patient with HF+ADRD is 4 years older than the average non-ADRD HF patient and rates of hypertension, diabetes, renal failure, lung disease, vascular disease and frailty are all higher among HF+ADRD patients (p<0.001;
Table 1
). Differences in 30-day and 1-year readmission rates are statistically significant, but relatively small. (30-day: 23% vs. 25%; 1-year: 64% vs. 66% ,p<0.001). However, 30-day and 1-year mortality rates are markedly higher for HF+ADRD patients (30-day: 5% vs. 10%; 1-year: 30% vs. 49%).

Conclusions:
Thirteen percent of HFrEF patients have concurrent ADRD. On average, this population is older, frailer and has more comorbidities than HFrEF patients without ADRD. While readmission rates are similar, HF+ADRD patients have markedly higher short and long-term mortality. Additional work is needed to understand how much of this increased mortality can be prevented with improved HFrEF care.
Abstract 10656: Patient-Level Phenotype Network Identifies a Unique Subgroup Defined by Mild Pulmonary Hypertension and Clinical Resilience
Authors: Wang Ruisheng , Maron Bradley
Published: March 2022

Background:
Mild pulmonary hypertension (PH) is associated with increased mortality; however, the determinants of resilience in this population are not known. Most risk models overlook relationships between variables. We hypothesized that a patient-patient network will identify novel parameters that inform survival in mild PH.

Methods:
We analyzed clinical and outcome data (N=87 variables) retrospectively for patients with mean pulmonary artery pressure 19-24 mmHg in the Veterans Affairs Clinical Assessment, Reporting, and Tracking database. A patient-patient network was assembled using Pearson correlation coefficients (|r|>0.5) using patients’ clinical variables. NetworkX was used to identify distinct network modules, and a feature selection method ranked variable importance for patient module assignment.

Results:
The cohort (N=4,551; 96.6% male, 68 [63-74] yr) included patients with a history of heart failure (43%) and hypertension (88%). The patient-patient network had 43,509 edges and N=20 modules (Figure, A), which were associated with a variable clinical profile. At a median follow-up of 1181 [565-1944] d, the all-cause mortality rate range was: 15.9% (M1) - 37.9% (M14). Compared to M2-20, mortality was significantly lower for M1 (P<0.0001) (Figure, B). The most important variable driving patient assignment to M1 was pulmonary artery compliance (6.0 [4.7-7.1] mL/mmHg; cohort-normalized value=2.7).

Conclusions:
The mild PH patient-patient network identified numerous subphenotypes that are associated with variable clinical and outcome profiles. Using this unbiased approach, pulmonary artery compliance was associated unexpectedly with resilience.
Abstract 10658: Patients Receive Better Care in a Traditional Randomized Trial Setting Than in a Pragmatic Quality Improvement Study: Potential Implications for Improvements in Care
Authors: Chapman Brittany , McMurray John J , Devore Adam D , Allen Larry A , Granger Bradi B , Pagidipati Neha J , Kaltenbach Lisa , Lopes Renato D , Granger Christopher B
Published: March 2022

Introduction:
Use of guideline-directed medical therapy (GDMT) is suboptimal in practice and often better in patients enrolled in clinical trials. We sought to investigate whether care differed for patients with heart failure with reduced ejection fraction (HFrEF) recently enrolled in a pharmaceutical trial versus those in a pragmatic implementation study.

Methods:
DAPA-HF was a randomized trial of dapagliflozin versus placebo that included patients with HFrEF, and standard background GDMT was required unless contraindicated or not tolerated. CONNECT-HF was a site-level cluster randomized pragmatic trial that included patients discharged after admission for decompensated HFrEF, with the goal of improving GDMT at one year. Each study required patient informed consent. Medication use data includes the total population at the time of enrollment in DAPA-HF and at one year in CONNECT-HF.

Results:
CONNECT-HF enrolled U.S. patients who were younger, more likely female, and more often Black (Table 1). Patients in DAPA-HF had significantly higher use of all classes of GDMT at any dose and at ≥ 50% target dose (Figure 1). Unadjusted mortality was lower in DAPA-HF (Table 1).

Conclusions:
Use of GDMT was substantially better and mortality was lower in a traditional randomized trial than in a pragmatic implementation trial. Whether this is due to differences in the populations, site care teams, or intensity of care and monitoring is unknown. The protocol-driven aspects of traditional trials are worthy of further study to improve care provided in standard practice. These observations also support inclusion of patients in randomized trials given the excellent care and outcomes in that setting.
Abstract 10660: Genome-Wide Scan Identifies Variants Increasing Triglycerides Only Among Diabetics
Authors: Selvaraj Margaret , Paruchuri Kaavya , Haidermota Sara , Bernardo Rachel , Peloso Gina M , Natarajan Pradeep
Published: March 2022

Introduction:
Increased triglycerides (TG) frequently accompanies type 2 diabetes (T2D) mellitus and poor glycemic control. The extent to which genetics influences triglycerides differently in individuals with T2D is not well understood.

Methods:
We conducted a genome-wide association study (GWAS) of log(TG) stratified by T2D using imputed UKB genotypes with minor allele count>20. We used linear regression model with a leave-one-out cross-validation using REGENIE adjusted for PC1-10, age, age
2
, gender, array-type, and race. We assessed the heterogeneity (I
2
) between the effects of TG in T2D and non-T2D individuals. We sought replication in the Mass General Brigham Biobank (MGBB).

Results:
Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 17 and 45 loci significantly associated with TG levels, respectively. Only one loci exhibited significant genome-wide heterogeneity (I
2
=98.4%; p
heterogeneity
=2x10
-15
). The most significantly heterogenous variant was an intronic variant of the
HLA-DQB1
gene, where the major allele (frequency 91.3%) was associated with increased TGs among those with T2D but not non-T2D (T2D group: beta=0.066, p-value=3.9x10
-15
; non-T2D group: beta=-0.002, p-value=0.21). Among 25,136 participants (6,951 T2D cases) of MGBB, we replicated this finding (p
heterogeneity
=0.01).

Conclusions:
An intronic variant at
HLA-DQB1
significantly associates with increased TGs only in those with T2D.
Abstract 10663: Outcomes After Heart Transplantation in Patients with Cardiac Sarcoidosis
Authors: Alvarez Paulino , Asleh Rabea , Alnsasra Hilmi , Doulamis Ilias P , Kampaktsis Polydoros , Kushwaha Sudhir , Briasoulis Alexandros
Published: March 2022

Introduction:
The number of patients with sarcoidosis requiring heart transplantation (HT) is on the rise.

Hypothesis:
The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy.

Methods:
Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Moreover, we reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single-center.

Results:
A total of 30,874 HT recipients were included in the present study (n=240 sarcoidosis, n=1,431 non-ischemic restrictive cardiomyopathy, and n=29,203 non-ischemic dilated cardiomyopathy). During a total of 196,985 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischemic dilated cardiomyopathy (adjusted subhazard ratio [aSHR] 1.4, 95% confidence intervals [CI]: 0.88-2.3, p=0.15) or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, p=0.67). Accordingly, multivariable analysis suggested that 1-year mortality was not significantly different between sarcoidosis and non-ischemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, p=0.12) or restrictive (aSHR 1.15, 95% CI: 0.61-2.18, p=0.66) cardiomyopathy. Additionally, no differences were observed regarding 30-day mortality after HT. Data from the single-center case review showed excellent long-term outcomes with sirolimus-based immunosuppression.

Conclusions:
Short- and long-term outcomes after isolated HT do not seem to be inferior in sarcoid cardiomyopathy when compared to common types of non-ischemic cardiomyopathy.
Abstract 10664: Quantitative T2 Mapping to Diagnose Cardiac Sarcoidosis and Predict Incident Heart Failure
Authors: Aquino Gilberto , Chamberlin Jordan , Wortham Andrew , Rieter William , James Ennis , Houston Brian A , Varga-Szemes Akos , Stringer Natalie , Kocher Madison , Waltz Jeffrey , Mercer Megan , Burt Jeremy R
Published: March 2022

Introduction/Hypothesis:
Myocardial native T2 quantification using cardiac magnetic resonance (CMR) may be helpful to diagnose active cardiac sarcoidosis and predict prognosis without the need for IV gadolinium.

Methods:
At a large academic institution, 66 consecutive patients with biopsy-proven pulmonary sarcoidosis underwent CMR for evaluation of active cardiac sarcoidosis (CS) from January 2017 to January 2020. Of these, 56 patients were identified who fit inclusion criteria. Active clinical CS was defined according to the Japanese Ministry of Health and Welfare criteria for diagnosis of CS. Quantitative T2 mapping of all AHA myocardial segments was evaluated and incident heart failure (HF) was recorded. A power calculation was performed beforehand which suggested n > 50 was adequate.

Results:
The best fit model to identify active clinical CS was the mean T2 value of the basal segments (AUC 0.902, 95% CI 0.821-0.983; see Figure 1). Mean basal T2 >51 ms was the optimal cutoff with accuracy of 91.1%, sensitivity of 71.4%, and specificity of 97.6%. T2 >49 ms was the most sensitive cutoff (92.9%) with a negative predictive value of 96.2%. The best fit model to predict incident HF was the average T2 value of the basal segments (AUC 0.830, 95% 0.702-0.959). For every 1 ms increase in T2 value, there was a 41% increased risk for incident HF (odds ratio 1.41 95% CI 1.12-1.92, p=0.013).

Conclusion:
Measurement of mean basal myocardial T2 values efficiently identified patients with active clinical cardiac sarcoidosis and predicted incident heart failure. Quantitative T2 mapping is highly sensitive and specific for the diagnosis.
Abstract 10667: Psychosocial Predictors of Cardiovascular Disease Risk Among Older Persons with HIV
Authors: Irwin Crista , Higgins Melinda , Waldrop Drenna , Gary Rebecca
Published: March 2022

Introduction:
People with HIV (PWH) are twice as likely to develop cardiovascular disease (CVD) at an average of 8 years earlier than persons without HIV independent of known risk factors; as a result, CVD is a major cause of morbidity and mortality in older PWH. Traditional CVD risk calculators do not reliably predict CVD in PWH. Psychosocial factors have been linked to higher rates of CVD in persons with and without HIV and PWH report higher rates of depression.

Hypothesis:
Clinical and psychosocial predictors were examined for associations with CVD risk scores among PWH.

Methods:
Clinical measures including blood pressure, cholesterol, CVD medications, smoking status and comorbidities were extracted from electronic medical records of PWH aged 40 years and older. CVD risk scores were calculated using the Atherosclerotic Cardiovascular Disease (ASCVD) calculator. Psychosocial factors were measured by the Perceived Stress Scale, the Internalized HIV Stigma Scale, Beck’s Depression Index-II, and the PROMIS-Sleep Disturbance and Emotional Support Scales. Multiple linear regression was used to examine associations between CVD risk scores and clinical/psychosocial variables. Covariates included age, gender, and race, and education.

Results:
Of the n=90 participants, the majority were male (n=52, 57.8%) and African American (n=77, 85.6%). Overall, the average CVD risk score for the total sample was low (mean 10.6, SD 7.0). Older age, which was significantly associated with higher CVD risk scores, is included in the ASCVD calculation, therefore, age was excluded from the model. Psychosocial variables and other covariates were examined with CVD risk scores and higher depressive symptom scores explained 6% of the variance (adj r
2
=0.061, p=0.01). No additional clinical or psychosocial variables were significant.

Conclusions:
The low ASCVD risk scores suggests that other factors such as chronic inflammation may contribute to higher CVD rates in this population and merits further research. Older age and higher depressive symptoms were significantly associated with CVD greater risk which may be bidirectional. Screening for depressive symptoms during routine clinic visits may provide a window of opportunity to reduce CVD burden in older PWH.
Abstract 10677: Skeletal Muscle Sirt3 Deficiency-Mediated Loxl2 Secretion in Remote Pulmonary Vascular Remodeling and Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction
Authors: Jheng Jia-rong , Noda Kentaro , Halliday Gunner , Bai Yang , Joshua Huot R , Cook Todd , Goncharov Dmitry A , Frump Andrea L , Goncharova Elena , Simon Marc , Forman Daniel E , Rojas Mauricio , Bonetto Andrea , MacHado Roberto F , Gladwin Mark T , Lai Yen
Published: March 2022

Background:
Pulmonary hypertension in the context of heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide. However, major pathways involved in the regulation of PH-HFpEF are still not well understood. We have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. In this study, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF.

Methods and Results:
Skeletal muscle-specific
Sirt3
knockout mice (
Sirt3
skm-/-
) exhibited drastically reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Using global mass spectrometry-based comparative secretome analysis, we found elevated secretion of lysyl oxidase homolog 2 (LOXL2) in SIRT3-deficeint skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of
Sirt3
skm-/-
mice, rats with experimental PH-HFpEF (SU5416/Obese ZSF1, Ob-Su), and patients with PH-HFpEF. Interestingly, expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX), which plays a housekeeping role in repressing cellular proliferation, were decreased in PASMCs from
Sirt3
skm-/-
mice. Reduced WWOX expression levels were also detected in PASMCs from Ob-Su rats and human subjects with obesity and diabetes. Treatment with LOXL2 recombinant protein resulted in reduced WWOX expression
ex vivo
in precision-cut lung slices (PCLS) and
in vitro
in PASMCs. Media conditioned by SIRT3-deficient skeletal muscle cells reduced WWOX expression in PASMCs, concomitant with increased PCNA levels and cellular proliferation. Finally, knockdown of both SIRT3 and LOXL2 in skeletal muscle cells or suppression of LOXL2 with β-aminopropionitrile (BAPN) restored WWOX and PCNA levels in PASMCs.

Conclusions:
These studies indicate a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. These studies also reveal a new endocrine signaling axis that links skeletal muscle SIRT3 deficiency to remote WWOX regulation in the pulmonary vasculature through myokine LOXL2.
Abstract 10678: Butyrate Improves Energetics, Diastolic Function and Contractile Reserve in Hearts from Mice with Hypertrophic Cardiomyopathy Due to Myosin R403Q Mutation
Authors: Baka Tomas , Croteau Dominique , Chambers Jordan , He Huamei , Balschi James , Qin Fuzhong , Colucci Wilson S , Pimentel David , Luptak Ivan
Published: March 2022

Background:
It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy starved as reflected by a decreased phosphocreatine to ATP ratio that corresponds to increased ADP and decreased free energy of ATP hydrolysis (ΔG
~ATP
). Notably, worsened energetics precedes hypertrophy in development of HCM and mitochondrial mutations impeding ATP synthesis frequently lead to a hypertrophic phenotype similar to HCM. It remains unclear whether targeted strategies to boost mitochondrial ATP synthesis may improve chronically depressed diastolic function and contractile reserve. Here we hypothesize that saturating mitochondria with an accessible substrate, butyrate, acutely improves energetics and function in HCM.

Methods and Results:
Isolated hearts from 6 months old mice with HCM due to R403Q myosin mutation (R403Q) vs. the wild type littermates (WT) were studied using
31
P NMR spectroscopy to measure ATP synthesis, ADP and ΔG
~ATP
at low (LW) and high workload (HW) and HW plus 4 mM butyrate (HWB). As expected, compared to WT, R403Q hearts showed: ↑ATP synthesis associated with a trend for ↑rate pressure product (RPP, p=0.08) at LW but were unable to increase these parameters further at HW. Energetics (↑ADP and ↓ΔG
~ATP
) were depressed at LW and worsened further at HW. Diastolic dysfunction (↑EDP) developed at HW. Butyrate perfusion (HWB) significantly improved all energetic and contractile parameters in R403Q hearts.

Conclusion:
Here we show that mouse hearts with HCM due to myosin R403Q mutation have worsened energetics despite a higher ATP synthesis rate at baseline. With higher work demand R403Q hearts are unable to dynamically increase ATP synthesis or work. Acute saturation with butyrate enables a further increase in ATP synthesis, normalizing energetics and improving diastolic function and contractile reserve. Thus, our results suggest that targeting mitochondrial function may be a promising strategy in management of HCM.
Abstract 10681: Effect of Low vs. High Home-Based Walking Exercise on Physical Activity in Patients with Peripheral Artery Disease: The Lite Randomized Clinical Trial
Authors: Slysz Joshua , Spring Bonnie , Rejeski W. Jack , Manini Todd , Guralnik Jack , Forman Daniel E , Tian Lu , Zhao Lihui , Zhang Dongxue , McDermott Mary M
Published: March 2022

Objective:
In a randomized clinical trial of people with lower extremity peripheral artery disease (PAD), to test whether walking exercise conducted at a pace without ischemic leg symptoms improved physical activity more than walking exercise conducted at a pace that induced ischemic leg symptoms and more than an attention control group.

Methods & Results:
In the LITE multi-centered clinical trial, 305 participants with PAD (69±40 years, 181 (59%) black, 146 (48%) female) were randomized to: 1) walking exercise conducted at a comfortable pace without ischemic leg symptoms (low-intensity), 2) walking exercise conducted at a pace eliciting ischemic leg symptoms (high-intensity), or 3) an attention-control group for 12-months. Physical activity (i.e., activity counts per minute) was a pre-specified secondary outcome. Both exercise groups were asked to walk for exercise in an unsupervised setting for up to 5 times/week for up 50 minutes/session. Physical activity was measured for up to 10 days using an ActiGraph accelerometer at baseline, 6-month, and 12-month follow-up. Low intensity exercise increased physical activity significantly less than high intensity exercise at 6-month follow-up (-74 counts per minute, 95% CI: -123, -26, P=0.003; Table 1) and 12-month follow-up (-47 counts per minute, 95% CI: -79, -15, P=0.004; Table 1). High intensity exercise increased physical activity significantly more than control at 6-month follow-up (+104 counts per minute, 95% CI: 48, 162, P<0.001; Table 1) and 12-month follow-up (+55 cpm, 95% CI: 18, 93, P=0.004; Table 1). There was no difference between the low intensity group and control at 6-month or 12-month follow-up (Table 1).

Conclusion:
These results support home-based walking exercise conducted at a pace that induces ischemic leg symptoms, but not walking exercise conducted at a comfortable pace without ischemic leg symptoms, to improve physical activity in people with PAD.
Abstract 10682: Peripartum Myocardial Strain Analysis: A Marker for Adverse Cardiovascular Outcomes?
Authors: Zadikany Ronit , Lauzon Marie , Kilpatrick Sarah , Wei Janet
Published: March 2022

Introduction:
Hypertensive disorders of pregnancy (HDP) contribute significantly to adverse cardiovascular (CV) outcomes in peripartum women, and echocardiography helps stratify risk and guide management. Global longitudinal strain (GLS), a marker of left ventricular (LV) systolic function, has not been well-characterized in peripartum women with or without HDP.

Hypothesis:
We hypothesized that GLS is abnormal in women with prior HDP and may predict adverse CV outcomes.

Methods:
We retrospectively analyzed 141 women with echocardiograms performed during the peripartum period (6 weeks antepartum to 8 weeks postpartum). We investigated relationships between adverse CV outcomes and clinical and echocardiographic variables, including peak systolic GLS. Prior HDP was defined as a preceding diagnosis of gestational hypertension (HTN), chronic HTN or preeclampsia.

Results:
Women with prior HDP (72/141, 51%) were older (35 vs 32 years), more often obese (61% vs 34%) and had higher mean arterial pressure (96 vs 82 mmHg) compared to those without prior HDP (p<0.01 for all). Women with prior HDP had greater LV thickness (1.0 vs 0.9 cm) and more frequently abnormal inferior vena cava (IVC) size and collapsibility (p<0.01 for all), although median LV ejection fraction (64% vs 65%) and GLS (-19.6 vs -20.2) were similar. During follow-up of 2.5 years, women with prior HDP had more CV-related emergency department (ED) visits (36% vs 16%, p<0.01) and hospitalizations (32% vs 12%, p<0.01). Using multivariable modeling, left atrial area (LAA) and IVC size better predicted CV-related ED visits and hospitalizations when compared to age, obesity and history of gestational HTN (
Figure
).

Conclusions:
Although GLS did not predict CV outcomes, abnormal LAA and IVC suggest elevated left and right atrial pressure is related to HDP and CV outcomes. Further study of LV diastolic or right ventricular dysfunction may elucidate mechanisms contributing to adverse outcomes in this population.
Abstract 10685: Right Ventricular-Pulmonary Arterial Coupling in Heart Failure Patients with Secondary Mitral Regurgitation: Analysis from the COAPT Trial
Authors: Brener Michael I , Grayburn Paul , Lindenfeld Joann , Burkhoff Daniel , Liu Mengdan , Zhou Zhipeng , Alu Maria , Medvedofsky Diego A , Asch Federico M , Weissman Neil J , Bax Jeroen J , Abraham William T , Mack Michael , Stone Gregg W , Hahn Rebecca T
Published: March 2022

Objectives:
We sought to determine the prognostic impact of right ventricular (RV) function characterized by RV-pulmonary arterial (PA) coupling in heart failure (HF) patients with severe secondary mitral regurgitation (SMR) enrolled in the COAPT trial.

Background:
RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) versus guideline-directed medical therapy (GDMT) has not been examined.

Methods:
We assessed RV-PA coupling by the ratio of RV free wall longitudinal strain (FWLS) derived from speckle-tracking echocardiography (STE) and non-invasively measured RV systolic pressure (RVSP). Advanced RV-PA uncoupling was defined by RVFWLS/RVSP ≤0.5. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up.

Results:
A total of 372 patients underwent STE, among whom 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR 1.87, 95% CI 1.31-2.66, p=0.0005). A similar association was present for all-cause mortality alone (HR 2.57, 95% CI 1.54-4.29, p=0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. TEER improved 2-year outcomes both in patients with (48.0% vs. 74.8%, HR 0.51, 95% CI 0.37-0.71) and without (28.8% vs. 47.8%, HR 0.51, 95% CI 0.27-0.97) advanced RV-PA uncoupling (pinteraction=0.98).

Conclusions:
In the COAPT trial, advanced RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes (
Figure 1
), reinforcing the importance of RV dysfunction in patients with HF.