bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12309: Effects of Sex and Age on Plasma Fatty Acids as Measured by Gas Chromatography/Mass Spectrometry in a Very Large Population Analysis
Authors: Diffenderfer Margaret R , Rajapakse Nandani , Pham Ericka , He Lihong , Nelson John R , Schaefer Ernst J
Published: April 2022

Background:
Studies have documented the beneficial effects of omega-3 fatty acids, specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as found in oily fish and/or fish oil capsules, on cardiovascular disease (CVD) risk reduction. JELIS using purified EPA 1800 mg/day and REDUCE-IT using EPA 4 g/day reported significant reductions in CVD endpoints in statin-treated subjects versus controls. Median plasma EPA levels increased from 97 to 166 μg/mL in the treatment group in JELIS and from 26 to 169 μg/mL in REDUCE-IT. Reductions in CVD endpoints were related to EPA levels. No benefit on CVD risk was observed in STRENGTH, when subjects were given 4 g/day of a carboxylic acid formulation containing both EPA and DHA.

Objective:
We aimed to ascertain interrelationships of sex and age with plasma fatty acids, especially omega-3 fatty acids, in a very large clinical population.

Methods:
Plasma fatty acids were measured by gas chromatography/mass spectrometry after lipid extraction in 1,169,621 fasting United States subjects (56.2% female; median age 58.2 yr).

Results:
Plasma fatty acid indices (median±IQR), expressed as percentage of total fatty acids, were 31.5±1.5% for saturated fatty acids (sum of 14:0, 16:0, and 18:0); 21.4±2.2%, monounsaturated fatty acids (sum of 16:1n7-
cis
and 18:1n9-
cis
); 0.45±0.23%,
trans
fatty acids (sum of 16:1n7-
trans
and 18:1n9-
trans
); 42.4±3.0%, omega-6 fatty acids (sum of 18:2n6, 20:3n6, and 20:4n6); and 2.55±0.80%, omega-3 fatty acids (sum of 20:5n3 and 22:6n3). EPA plasma levels were 22.0±9.6 μg/mL (median±IQR), significantly lower than levels ≥150 μg/mL required for significant CVD risk reduction in randomized trials. Females had significantly (
P
<0.0001) lower indices of monounsaturated (-4.31%) and
trans
fatty acids (-9.30%) and significantly higher indices of omega-6 (+2.79%) and omega-3 fatty acids (+6.82%) than males. Older subjects (≥65 years of age) had a significantly (
P
<0.001) higher median omega-3 fatty acid index (+29.68%) and higher plasma EPA levels (+57.05%) than younger subjects (<30 years of age).

Conclusion:
In one of the largest US population studies looking at fatty acids, we found sex and age specific differences. Plasma EPA levels were very low in all groups.
Abstract 12314: Clinical Determinants of Low Attenuation Epicardial Adipose Tissue Volume in Type 2 Diabetes
Authors: Ayton Sarah L , Yeo Jian L , Gulsin Gaurav S , Brady Emer M , Arnold Jayanth R , Graham-Brown Matthew P , Singh Anvesha , Dey Damini , McCann Gerry P , Moss Alastair J
Published: April 2022

Introduction:
The accumulation of excess epicardial adipose tissue (EAT) is associated with the onset of specific heart failure phenotypes. Subsets of adipocytes in EAT produce an inflammatory secretome which alters the extracellular matrix of the epicardium and impairs myocardial contractility. Lipid-laden adipocytes have a low computed tomography (CT) attenuation and can be readily identified using cardiac CT.

Objective:
This study sought to identify the clinical and biomarker determinants of low attenuation EAT in participants with Type 2 diabetes (T2D) at risk of heart failure.

Methods:
Participants with T2D and non-diabetic controls were prospectively recruited to an observational multi-modality cardiovascular imaging study. Deep learning analytics (QFAT, Cedars-Sinai) measured EAT volume and CT attenuation from cardiac CT datasets. Adipose tissue with CT attenuation values of -90 to -190 Hounsfield Units (HU) were classified as low attenuation EAT regions. Comparison was made with anthropometric and blood biomarkers to evaluate determinants of low attenuation EAT.

Results:
Type 2 diabetic (n=151, median age 64 (59, 69) years, 65% male) and non-diabetic individuals (n=39, median age 59 (54, 66.5) years, 59% male) were recruited. Total EAT volume indexed to body surface area was 1.6-fold higher in diabetics (62.4 (49.1, 77.7) cm
3
/m
2
vs 38.8 (29.6, 51.9) cm
3
/m
2
, p <0.01) and mean CT attenuation was lower (-77.4 +/- 5.2 HU vs -70 +/- 5.4 HU, p <0.01). Larger indexed EAT volume was associated with a lower mean CT attenuation in all participants (r = -0.839, p <0.01). Multivariate analysis identified increasing age, white ethnicity and waist circumference as independent determinants of low attenuation EAT (adjusted R
2
= 0.2003, p <0.01). No association was found with dysglycemia (HbA1c, p = 0.2), dyslipidemia (Triglycerides, p = 0.1) and subclinical inflammation (neutrophil:lymphocyte ratio, p = 0.4).

Conclusions:
In patients with T2D, indexed EAT volumes are 1.6-fold higher with a lower mean CT attenuation. Age, white ethnicity and waist circumference are associated with low attenuation EAT. Prospective studies are required to determine whether interventions to reduce low attenuation EAT will prevent the onset of heart failure.
Abstract 12315: Circulating Gut Microbial Peptides Aggravate Cardiac Inflammation and Promote DNA Hypomethylation at the TLR-2 Promoter Region in Type 2 Diabetic Mice
Authors: Prasad Ram , Kansal Vikash , Ranjan Prabhat , Verma Suresh K , Grant Maria
Published: April 2022

Introduction:
Epigenetic modifications, especially DNA methylation, influence key biological processes, including inflammation, and are considered as a “switch” between gene silencing and gene activation. Promoter DNA hypomethylation activates TLR-2, a modulator of inflammation, and may impact cardiac function in T2D.

Hypothesis:
The gut microbial peptide peptidoglycan (PGN) enters the circulation via a leaky gut and activates TLR-2 in cardiac tissue by DNA hypomethylation contributing to cardiac dysfunction in T2D.

Methods:
T2D (
db/db
) and wild-type mice were euthanized after four months of diabetes. Assessment of gut permeability, gut and systemic inflammation, and hypomethylation (5hmC) of cardiac tissue was performed using IHC, qPCR, ELISA, and western blot analysis. In-vitro studies were conducted in PGN-treated cardiomyocytes with and without 2-hydroxyglutarate (2HG).

Results:
db/db mice showed cardiac dysfunction as measured by reduced percent of LVEF (46.2±2.7
vs.
65.8±1.8; p<0.001), LVFS(22.7±1.6
vs.
35.4±1.3; p<0.001), and increased LV mass (192.4±17.0
vs.
105.8±12.4; p<0.006) compared with WT controls.
db/db
mice also exhibited higher gut permeability as observed by reduction of tight junction proteins (ZO-1, p120-catenin, and β-catenin) and increased levels of plasma FABP-2. The levels of PGN were higher in plasma (84.19 ± 13.56
vs.
27.21 ± 8.4; p<0.003) and cardiac tissue (1361 ± 236.1
vs.
113 ± 25.58; p<0.001) of
db/db
mice. The expression of TLR-2 (2.26 folds; p<0.003), pro-inflammatory cytokines IL-1β (p<0.008), and TNF-α (p<0.0004) were significantly up-regulated compared to WT mice. Expression of 5hmC was significantly higher (18.48±1.32
vs.
5.91±0.28; p<0.001) in the hearts of diabetic mice. Increased expression of 5hmC, ten-eleven translocation 1-3 (TET-1, 2, 3), IL-1β, IL-6, and TNF-α were also observed in PGN treated cardiomyocytes. 2HG treatment blocked PGN- mediated DNA hypomethylation and inflammation in cardiomyocytes.

Conclusions:
Circulating gut peptides have deleterious effects on cardiac health in diabetic mice by promoting DNA hypomethylation of
TLR2
and increased inflammation. Strategies aiming to restore gut barrier integrity may beneficially impact diabetic cardiovascular complications.
Abstract 12316: Carnitine O-octanoyltransferase Inhibition Attenuates Human Aortic Valve Interstitial Cell Calcification by Correcting Energetic Mitochondrial State
Authors: Okui Takehito , Iwashita Masaya , Rogers Maximillian A , Kuraoka Shiori , Halu Arda , Sawada Yoshikazu , Aikawa Masanori , Singh Sasha A , Aikawa Elena
Published: April 2022

Background:
Cardiovascular calcification is a critical pathology associated with increased cardiovascular risk, but there are no FDA-approved anti-calcification therapies. Through an unbiased screening approach, we previously identified carnitine O-octanoyltransferase (CROT) as a novel contributing factor to vascular calcification, but whether it can inhibit calcification in cardiac valves remains unknown. Here we investigated CROT-associated mechanisms of calcification in human valvular interstitial cells (VICs).

Methods and Results:
Human VICs were isolated from aortic valve leaflets of patients undergoing valve replacement surgeries at Brigham and Women’s Hospital, and cultured in osteogenic medium (OM) to induce calcification. OM increased CROT mRNA expression (1.83±0.41 fold-change; p<0.05). Tissue-nonspecific alkaline phosphatase activity, a key regulator of calcification, was also increased by OM (8.80±3.81 fold-change; p<0.001) and reduced by CROT siRNA treatment (0.48±0.19 fold-change; p<0.01). CROT siRNA decreased calcium deposition (Alizarin red staining; >99.9%; p<0.001). We previously showed that mitochondria dysfunction contributes to vascular calcification. We therefore, assessed mitochondrial function in VICs by measuring oxygen consumption rate and extracellular acidification rate. Basal and maximal respiration, spare respiratory capacity and ATP production increased in VICs after OM stimulation (1.73±0.48, p<0.01; 1.75±0.34, p<0.01; 2.11±0.63, p<0.05; 1.75±0.38, p<0.05; respectively), indicating mitochondrial dysfunction. These parameters were corrected to normal state followed by CROT siRNA treatment. The combined data of oxygen consumption and extracellular acidification rates indicated that osteogenic condition induced mitochondria energetic state that was corrected to quiescent state by CROT siRNA treatment.

Conclusions:
CROT promotes calcification of human aortic VICs. CROT inhibition attenuates the calcification of VICs via correcting mitochondrial dysfunction induced by osteogenic environment. CROT inhibition is an attractive approach as a therapy for aortic valve calcification, a major unmet medical need.
Abstract 12501: Admission Serum Chloride Concentrations and Mortality Outcomes in Heart Failure Patients
Authors: AMORAN OLAYIWOLA , Chaudhury Ankur , Singh Harpreet , Kohut Andrew
Published: April 2022

Introduction:
Acute decompensated CHF is associated with a number of electrolyte abnormalities. Hyponatremia has been well established as having a close association with mortality in CHF patients, however in the past decade several robust retrospective studies have raised the intriguing possibility that chloride levels may be as or more significant than sodium levels as a mechanistic player in the pathophysiology of CHF, and a potential target for future therapeutics.

Hypothesis:
Admission chloride is related to all-cause mortality in CHF patients, even when adjusted for LVEF.

Methods:
96 patients admitted to the Hospital of the University of Pennsylvania between 1/1/2017 and 12/31/2019 with a diagnosis of acute decompensated CHF were selected. The relationship between admission chloride on first admission during which patient received IV diuretics and all-cause mortality was analyzed by univariate regression, with multivariate adjustment for LVEF.

Results:
Per our univariate Cox proportional hazards regression model, admission chloride was inversely related with all-cause mortality in our population of CHF patients (HR per unit change 0.925; 95% CI: 0.864-0.990; p<0.05) indicating a ~7.5% relative improvement in survival per unit increase in chloride. After multivariable adjustment for LVEF, admission chloride remained independently inversely related with mortality (HR per unit change 0.923; 95% CI: 0.859-0.991, p<0.05). After multivariable adjustment for admission sodium however, admission chloride lost its significance with mortality (HR per unit change 0.953; p=0.213).

Conclusions:
Our study confirms that chloride levels are an important predictor of all-cause mortality in CHF patients, independent of LVEF. Figure 1 visually illustrates the worsening of cumulative mortality in patients within the lowest chloride tertile, although our Kaplan Meier survival curves remained just outside the bounds of significance (p=0.052).
Abstract 12502: Transcatheter Patent Ductus Arteriosus Closure is Associated With Improved Outcomes Compared to Surgical Ligation
Authors: Kuntz Michael T , Staffa Steven J , Graham Dionne , Faraoni David , Levy Philip , DiNardo James , Maschietto Nicola , Nasr Viviane G
Published: April 2022

Introduction:
Pharmacologic therapy for closure of a patent ductus arteriosus is not consistently successful. Surgical ligation (SL) or transcatheter closure (TC) may be needed. Large multi-center analyses comparing outcomes and resource utilization between SL and TC are lacking. We hypothesized that patients undergoing TC have improved outcomes compared to SL including mortality, length of stay (LOS), intensive care unit (ICU) admission, and ventilation.

Methods:
Using the 2016-2020 Pediatric Health Information System database, characteristics, outcomes, and charges of patients less than 1 year who underwent TC or SL were analyzed.

Results:
678 inpatients undergoing TC (n=503) or SL (n=175) were identified. Surgical patients were younger (0.1 vs 0.53 yrs; P<0.001) and more premature (60% vs 20.3%; P<0.001). Comorbidities were more prevalent among SL patients: bronchopulmonary dysplasia (28.6% vs 16.3%; P<0.001), necrotizing enterocolitis (9.7% vs 0.4%; P<0.001), intraventricular hemorrhage (21.7% vs 2.4%; P<0.001), sepsis (11.4% vs 0.6%; P<0.001), and renal insufficiency (7.4% vs 0.8%; P<0.001). Over time, TC represented an increasing proportion of cases (Figure 1). In-hospital mortality for TC was 0% vs 1.7%; P=0.02. Using inverse probability of treatment weighting by the propensity score, multivariable adjusted analyses demonstrated favorable outcomes in TC: ICU admission rates (adjusted odds ratio (aOR): 0.2; 95% CI: 0.11, 0.32; P<0.001); mechanical ventilation (aOR: 0.3; 95% CI: 0.19, 0.56; P<0.001); and shorter hospital (adjusted coefficient: 2 days shorter; 95% CI: 1.3, 2.7; P<0.001) and postoperative (adjusted coefficient: 1.2 days shorter; 95% CI: 0.1, 2.3; P=0.039) LOS. Overall charges (adjusted coefficient: -$13,100, 95% CI: -26,400, 200; P=0.06) and readmission rates were similar.

Conclusions:
TC is associated with better outcomes including mortality and LOS. Rates of TC continue to increase compared to SL.
Abstract 12517: CardioSignal Smartphone Application Detects Atrial Fibrillation in Heart Failure Population
Authors: Blomster Juuso , Lahdenoja Olli , Jafarian Dehkordi Kamal , Kaisti Matti , Tapiovaara Tero , Santalahti Kristiina , Pankaala Mikko
Published: April 2022

Introduction:
The micro-electromechanical sensors of a common smartphone can be used to detect vibrations caused by cardiac motion when the smartphone is placed on chest. With commonly available CardioSignal application (App) the concept has been shown to detect atrial fibrillation (AFib) in clinical setting from a 60 second recording. The CardioSignal smartphone app is a certified CE IIa-class medical device and intended to detect AFib in adult population. AFib and heart failure (HF) frequently coexist and together can lead to increased morbidity. To address this subgroup of individuals with increased risk of Afib, we examined how CardioSignal solution performs in Afib detection in a population of recent HF decompensation.

Methods:
From a total of 83 HF patients (mean age 64, 70 % men) motion sensor signals were collected and analyzed with the CardioSignal solution. The signals were collected by placing a smartphone on the chest of the patients in supine position. From the recordings two 60 second strips were analyzed. A simultaneous 1-lead ECG data was collected with an ECG patch from the V4 position. The signals were analyzed for quality and rhythm diagnostics from the ECG recording was by a cardiologist blinded for the CardioSignal solution result. Finally a head-to-head comparison was conducted for CardioSignal result and the ECG data. A positive finding for Afib was concluded if both 60 second recordings detected Afib for each person.

Results:
From the 83 HF patients 166 measurements were recorded. Out of the 166 measurements, 163 passed the quality check for the sensor signals. The preliminary analyses showed sensitivity of the AFib detection algorithm of 80.7% (95% CI 62.5% to 92.6%) and the specificity of 100.0% (93.1% to 100.0%). The positive predictive value was 100.0% and the negative predictive value 89.7% (80.9% to 94.7%). The accuracy was 92.8% (84.9% to 97.3%).

Conclusions:
A smartphone-based recording and analysis with CardioSignal solution in HF patients appear to be an effective and reliable method to detect possible Afib.
Abstract 12519: Electrocardiographic Findings and Arrhythmias in Patients With Familial ST-Depression Syndrome
Authors: Christensen Alex H , Vissing Christoffer , Villumsen Sofie , Pietersen Adrian , Tfelt-hansen Jacob , Jensen Thomas , Olesen Morten , Pehrson Steen , Henriksen Finn L , Sandgaard Niels , Iversen Kasper , Jensen Henrik , Bundgaard Henning
Published: April 2022

Background:
The recently reported Familial ST-depression syndrome is a distinct inherited cardiac disease entity characterized by persistent, non-ischemic ST-depressions and risk of arrhythmias and heart failure. We aimed at further characterizing the features associated with the syndrome.

Methods:
Retrospective analysis of demographics, electrocardiographic, arrhythmic and imaging data from families with Familial ST-depression syndrome in Denmark.

Results:
Forty affected individuals (43% men; mean age at diagnosis 49.1 years) from 14 apparently unrelated families with ≥2 affected members were included. Pedigree analyses were consistent with autosomal dominant inheritance in all families. The ST-depressions were most pronounced in leads V4, V5, and II and persisted over time (mean follow-up 9.3 years), i.e. no temporary normalization was seen. The ECG phenotype seemed to develop in pre-puberty. Exercise accentuated the ST-depressions with a maximum difference between rest/stress (mean) of -117μV in lead V5. Six (15%) patients developed ventricular arrhythmias or (aborted) sudden cardiac death, seven (18%) were diagnosed with left ventricular ejection fraction ≤50%, and 10 (25%) developed atrial fibrillation. Seven patients had at least one catheter ablation; five for supraventricular arrhythmias and two for ventricular arrhythmias. Males experienced more arrhythmic endpoints than females (Figure, p<0.01). Surprisingly, in some of the patients the ECG phenotype was tolerated for decades before events occurred.

Conclusions:
We identified 14 families with the novel syndrome showing autosomal dominant inheritance. The phenotype was associated with arrhythmias, aborted sudden cardiac death, or heart failure in about half of the cases. Families with Familial ST-depression syndrome should undergo cascade screening like in other inherited arrhythmia syndromes.
Abstract 12532: Extracellular Vesicles Released by Cardiosphere-Derived Cells Dampen the Pro-Inflammatory Monocyte Response Through Repression of C-C Chemokine Receptor Type 2 (CCR2)
Authors: Mentkowski Kyle I , Pandey Rohan , Schiffmacher Paul J , Eagler Lisa A , Reynolds Jessica L , Lang Jennifer K
Published: April 2022

Background:
Following a myocardial infarction (MI), CCR2+ monocytes migrate toward the injury site along a CCL2 concentration gradient and play an integral role in removing debris and facilitating repair. Although required to orchestrate the pro-inflammatory response, prolonged activation of CCR2+ monocytes can lead to adverse outcomes. Extracellular vesicles (EVs) derived from cardiosphere-derived cells (CDCs) have been suggested to mediate cardioprotection in part via immunomodulation. We hypothesized that CDC-EVs influence CCR2+ monocyte recruitment and function.

Methods:
Blood samples were obtained from healthy human donors under approved institutional IRBs. Human monocytes were isolated from peripheral blood using density gradient centrifugation (Ficoll) followed by magnetic activated cell sorting (MACS). EVs were isolated from CDCs, normal human dermal fibroblasts (NHDFs, an inert population in models of ischemia), and CDCs transfected with a miR-146a antagomir. EVs were characterized according to established guidelines for size, morphology and protein expression. Monocytes were incubated with PBS, NHDF-EVs, CDC-EVs, or miR-146a deficient CDC-EVs and analyzed for CCR2 protein expression by flow cytometry and western blot and migration along a CCL2/MCP-1 gradient by
in vitro
chemotaxis assays.

Results:
CDC-EVs significantly reduced CD14
hi
CD16
-
monocyte surface expression of CCR2 by 50% as quantified by flow cytometry when compared with PBS and NHDF-EVs (p<0.05, one-way ANOVA, n=4). This appeared to be mediated by miR-146a as monocytes treated with CDC-EVs deficient in miR-146a had no significant difference in CCR2 levels compared with cells treated with PBS and NHDF-EV controls. Importantly, reduced levels of monocyte CCR2 expression following CDC-EV treatment led to a greater than 35% functional reduction in monocyte migration towards CCL2 compared to PBS control (42.8 ± 3.2% vs. 68.3 ± 4.9%, p<0.05, t-test, n=4). CCR2 expression remained suppressed for 8-12 hours and could be maintained with repeated doses.

Conclusions:
CDC-EVs modulate classical monocyte expression of CCR2 and migration towards CCL2/MCP-1 via miR-146a, elucidating a novel mechanism of CDC-EV immunomodulation.
Abstract 12534: Incidence of Cardiotoxicity After Immune Checkpoint Inhibitor Therapy
Authors: Flint Danette , Moslehi Javid , Kearing Stephen , King Ashleigh , Gilstrap Lauren
Published: April 2022

Introduction:
Immune checkpoint inhibitors (ICI) have transformed care for cancer patients but can lead to immune-mediated toxicities in multiple organ systems. Cardiovascular toxicities are thought to be infrequent, but existing data likely underestimate this. We utilized Medicare claims data to define the incidence of cardiotoxicity after ICI therapy at a population level.

Methods:
We identified all fee-for-service beneficiaries who received an ICI, including CTLA-4 inhibitors, PD-1 inhibitors or PD-L1 inhibitors, between March 2011 through December 2018 using 100% Medicare Parts A and B. Demographic information, preexisting cardiac conditions, other comorbidities and cancer types were determined in the year prior to ICI exposure. Cardiac toxicities were identified using ICD-9/10 codes in the year after initial exposure.

Results:
In total, 40,676 patients were identified. Most (75%) received a PD-1 inhibitor and a significant minority (10%) received combination therapy. Across all ICI therapies, the incidence of myocarditis and related complications (ventricular arrhythmia, sudden cardiac death, heart block and cardiogenic shock) was 2.95% at one year. The incidence of acute decompensated heart failure was 10.76%, acute coronary syndrome 3.06% and death 1.92%. The highest incidence of myocarditis and associated cardiac diagnoses was seen with combination therapy (3.56%).

Conclusions:
Immune checkpoint inhibitors are associated with myocarditis and other serious cardiac toxicities. Results from our population level study suggest the incidence of cardiotoxicity after ICI exposure is likely higher than previously reported. The incidence of myocarditis and related complications is highest with combination therapy, as reported in prior studies.
Abstract 12535: The Hemodynamic Response to Exercise in Patients With Obstructive Hypertrophic Cardiomyopathy and the Effect of Metoprolol
Authors: Dybro Anne M , Rasmussen Torsten Bloch B , Nielsen Roni R , Ladefoged Bertil T , Andersen Mads , Jensen Morten K , Poulsen Steen H
Published: April 2022

Introduction:
Patients with obstructive hypertrophic cardiomyopathy (HCM) frequently experience advanced heart failure symptoms at low levels of physical activity. The relationship between symptoms and loading conditions during exercise is incompletely understood. Whether standard treatment with beta-blockers affects exercise hemodynamics is unknown.

Objectives:
The aim of this study was to investigate the invasive hemodynamic response to exercise in moderately symptomatic patients with obstructive HCM, and how treatment with metoprolol affects this response.

Method:
This double-blinded, placebo-controlled, randomized crossover trial enrolled 28 patients with obstructive HCM and New York Heart Association functional class ≥ II from May 2018 to September 2020. Patients received metoprolol or placebo for two consecutive two-week periods in random order. During each treatment period, patients underwent right-heart catheterization at rest and during exercise. The primary outcome was the difference in pulmonary capillary wedge pressure (ΔPCWP) between peak exercise and rest.

Results:
There was no treatment effect on Δ PCWP between metoprolol and placebo treatment (21(9) mmHg versus 23(9) mmHg; p = 0.12). When comparing metoprolol to placebo treatment, there was no significant difference in PCWP at rest (15 (6) mmHg versus 13 (5) mmHg; p = 0.06) or at peak exercise (35 (12) mmHg versus 37 (10) mmHg; p = 0.38). At peak exercise, metoprolol treatment was associated with a higher stroke volume (101 (24) ml versus 92 (21) ml; p < 0.01), a 25% lower heart rate (107 (19) beats/min versus 139 (23) beats/min; p < 0.0001), and subsequently a lower cardiac output (10.8 (3.3) L/min versus 12.8 (3.2) L/min; p < 0.0001).

Conclusion:
Exercise in patients with obstructive HCM is associated with a severe increase in left-sided filling pressures which are not affected by metoprolol treatment. Despite increased stroke volume during metoprolol treatment, cardiac output is reduced at peak exercise.
Abstract 12536: Nanoliposomal Treatment Reduces Stroke Injury Following Middle Cerebral Artery Occlusion in Mice
Authors: Ahmad Saif , Kindelin Adam , Truran Seth , Karamanova Nina , Lozoya Maria , Weissig Volkmar , Griffiths Daniel , Lifshitz Jonathan , Ducruet Andrew F , Migrino Raymond Q
Published: April 2022

Introduction:
Neuroprotective strategies for stroke are lacking leading to significant disability and death. Liposomes (phospholipid particles) are commonly used as molecular carriers of therapeutic agent cargos. We previously showed that cargo-less nanoliposomes (NL, <100 nm size particles) composed of phosphatidylcholine, cholesterol and monosialoganglioside (70:25:5 molar ratios) induced an antioxidant protective response in endothelial cells exposed to oxidative stress-mediated amyloid injury.

Hypothesis:
NL will preserve neuroblastoma cell viability in the setting of hypoxic injury and will reduce functional and histologic injury in mice following middle cerebral artery occlusion (MCAO).

Methods:
SH-SY5Y neuroblastoma cells were exposed to 20-hour physoxic (5% oxygen) condition or hypoxic (1% oxygen) condition without or with NL (100 or 300 μg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment scoring was compared as well as post-mortem brain infarction size.

Results:
Neuroblastoma cells showed reduced viability following hypoxia that was reversed by treatment with NL. NL increased gene expression of HO-1, NQO1 and SOD1 compared to untreated controls. NL-treated mice showed reduced neurologic function impairment and reduced brain infarct size compared to controls (18.8±2% versus 27.3±2.3%, p=0.017, see Figure).

Conclusions:
Cargo-less NL reduced functional and structural stroke injury in mice subjected to MCAO likely mediated in part through induction of an antioxidant stress response. NL is a candidate novel agent to mitigate stroke injury.
Abstract 12543: Limited Blood Biomarker Changes After Reverse Remodelling: A Markers and Response to CRT (Marc) Substudy
Authors: Maass Alexander H , Kloosterman Marielle , Voors Adriaan A , Vernooy Kevin , Meine Mathias , Allaart Cornelis , Vos Marc A , Cramer Maarten J , Van Gelder Isabelle C , Rienstra Michiel
Published: April 2022

Objectives:
Investigate if the amount of reverse remodelling after CRT coincides with blood biomarker changes.

Background:
Blood biomarkers are predictors of heart failure, but sparse data exist on the correlation between blood biomarkers changes and reverse remodelling.

Methods:
Fourteen blood biomarkers, reflecting collagen turnover (PIIINP, CICP, MMP-9, TIMP-1, ICTP), inflammation (hsCRP, IL-6), myocardial stretch and injury (NT-proBNP, hsTroponin-T), inflammatory-, fibrotic- and apoptotic pathways (Galectin-3, ST2, GDF-15) and renal function (creatinine, BUN), were assessed before and six months after CRT in 213 patients from the Markers and Response to CRT study. Additionally, baseline peripheral venous (PV) and coronary sinus (CS) samples were compared. Patients were divided in 4 groups based on indexed left ventricular end systolic volume change (LVESVi): no remodelling, lower, middle, and upper tertile.

Results:
Mean age was 66±10 years, 62% were men, 42% had ischemic aetiology. 169 patients experienced LVESVi reduction: lower tertile 12% (5-16%), middle tertile 32% (25-37%), upper tertile 53% (44-58%). Collagen markers increased in all groups. Inflammation markers remained in normal range. hsTroponin-T decreased in all groups. Renal markers showed no clinical significant change. GDF-15, ST2 and Galectin-3 remained elevated, showing no distinct pattern. Only NT-proBNP changes corresponded to LVESVi reduction (β -1.72, P<0.001). Between all CS-PV samples was a positive correlation (R-range: 0.72-0.97, all P<0.001).

Conclusions:
NT-proBNP changes are associated with amount of reverse remodelling 6 months after CRT. Thirteen other blood biomarkers, reflecting, among others, collagen turnover, fibrotic- and apoptotic pathways, are not. CS and PV samples correspond well, CS sampling does not seem to provide additional information in assessing reverse remodelling.
Abstract 12547: The Association of Serum Cholesterol and Statin Use With All-Cause Mortality Across Estimated Glomerular Filtration Rate (eGFR) Levels in United States Veterans and NHANES Cohorts
Authors: Arif Yousif , Marroquin Maria , Narasaki Yoko , Hsiung Jui-Ting , Soohoo Melissa , Kovesdy Csaba , Kalantar-Zadeh Kamyar , Rhee Connie , Streja Elani
Published: April 2022

Background:
Chronic kidney disease (CKD) patients have displayed a paradoxical association between total cholesterol (TC) and mortality, where CKD patients with elevated TC did not display an increased mortality risk. However, this TC-mortality relationship amongst CKD patients requires further study using large databases to assess the impact CKD stage, pharmacologic therapy, and patient population has.

Methods:
Retrospectively, two cohorts were studied using LIPROVET and NHANES data. Among the cohorts, there were 2,131,536 LIPROVET US veterans examined from 2004-2006 and 39,899 NHANES patients from 1999-2014. We examined the association of TC and statin use with all-cause mortality in patients with eGFR <60 and eGFR ≥60 mL/min/1.73m
2
using Cox Proportional Hazards model. Models were adjusted for demographics, comorbidities, smoking status, alcohol intake, income, education, laboratory measures, and medications. Those with TC≥200 mg/dL not on statin were used as reference.

Results:
The LIPROVET patients had a mean age of 63±14 and were 81% White and 5% female. LIPROVET patients with TC<200 mg/dL not on statin had a higher mortality risk compared to reference across all levels of adjustment and eGFR. Whereas those on statin, regardless of TC levels, had a lower to null mortality risk in the fully adjusted model. NHANES patients had a mean age 48±19 and were 46% White and 50% male. NHANES patients with TC<200 mg/dL not on statin had a trend of higher to null mortality risk compared to reference across eGFR groups after full adjustment. Those on statin, independent of TC levels, had a significantly lower mortality rate across all eGFR groups.

Conclusion:
Compared to patients with TC≥200mg/dL not on statin, patients with lower TC without statin had a higher mortality risk, while patients with statin had lower mortality risk regardless of TC level across all eGFR groups. Physicians may consider initiating or continuing statin therapy for CKD patients independent of TC level.
Abstract 12550: Overexposed? Evaluating the Need for Serial Surveillance Imaging Following Elective Aortic Hemiarch Replacement
Authors: Kemp Cenea , Ghincea Christian V , Gergen Anna K , Feng Zihan , McCabe Leighton , Krishnan Vishal , Rove Jessica Y , Cleveland Joseph , Fullerton David , Pal Jay , Aftab Muhammad , Reece T Brett
Published: April 2022

Introduction:
The optimal timing for imaging following ascending aortic replacement is unknown. Protocols currently differ based on institution. For the last 3 years, our institution has surveilled patients at 3 months, yearly for 3 years, and at 5 years following the operation.

Hypothesis:
We hypothesize surveillance CT scans performed at 3 months will identify any pathologies related to the ascending aortic repair that will require re-intervention; additional imaging may be superfluous.

Methods:
Using our single institution-maintained database, 311 patients who underwent an elective aortic hemiarch repair between February of 2010 and March of 2021 were identified. The timing for and stability of surveillance imaging was reviewed, paying special attention to pathology associated with the repair.

Results:
Of the 311 patients who underwent elective aortic hemiarch repair, 217 completed surveillance imaging. 187 patients had their initial imaging around 3 months following the operation, 85 patients completed imaging around one year, and 54 patients were imaged 2-8 years post-operatively with some patients undergoing multiple scans during this period. Nine patients required re-intervention; of these 9, four patients demonstrated pathology, on CT scan, associated with the actual ascending arch repair. Two patients developed a pseudoaneurysm (PSA), one at the distal aspect of the repair and one at the left ventricular outflow tract. The other two patients had degeneration of known distal aortic aneurysms. The two PSAs were intervened upon within the first 3 months and the degenerating aneurysms were intervened upon at 1 and 2.5 years post-operatively.

Conclusions:
These data support surveillance imaging completed at 3 months following ascending aortic replacement is sufficient to identify pathology related to the repair. While other indications may dictate ongoing surveillance, for most patients, the need for further imaging is potentially zero.
Abstract 12554: A Quality Improvement Program to Promote Assessment of Social Determinants of Health among Patients in an Urban Community Clinic
Authors: Hall Laura Lee L , POLLARD-THOMAS PAULA , Nuss Henry , Egwuogu Heartley , Ferdinand Keith , Hobbs Kristen , Echols Melvin
Published: April 2022

Introduction:
Social determinants of health (SDoH) have been linked to poorer health outcomes and health disparities among patients (pts) with heart failure (HF). Attainment rates of selected SDoH indicators vary depending on the pt care environment. We sought to assess whether there are challenges in collecting SDoH indicators in an urban community clinic through a Plan-Do-Study-Act (PDSA) method of quality improvement (QI) using a physician-medical assistant team (PMAT).

Methods:
Using PDSA QI methodology, a trained PMAT tested use of an EHR-based survey to measure and record selected SDoH at each pt-visit over a span of four weeks. The survey includes questions about financial resource strain, housing stability, transportation needs, food insecurity and alcohol use. The target for improvement was input of SDoH indicators for 90% of consecutive patient visits. Successful completion of the survey required recording of responses for all SDoH measures.

Results:
Prior to the PDSA, SDoH indicators were collected in 51% of the pts seen between Jan 2019 and Dec 2020. Between April 26 and May 21, 2021, 114 pts were seen by the PMAT, with the SDoH indicators recorded in 88% of the pt-visits (n=101). Weekly rates ranged from 76.9%-100% (Week 1, 30/30 pts (100%); Week 2, 24/29 pts (82.7%); Week 3, 27/29 pts (93.1%); and Week 4, 20/26 pts (76.9%).

Conclusion:
The PMAT successfully increased measurement and recording of SDoH factors, although the target goal for improvement was not completely met 2 of the 4 weeks. Personnel substitutions and variable approaches to accessing the survey tool in the EHR resulted in smaller rates of improvement. Nonetheless the PDSA demonstrated the feasibility of increasing SDoH measurement. Expansion of the QI program will focus on clinic-wide staff training, standardization of SDoH assessment tool access in the EHR, and linking patients to resources with demonstrated social and economic needs identified by the SDoH survey tool.
Abstract 12558: 3-year Outcomes In Stable Coronary Artery Disease Patients With Diabetes Based On A Novel Index: Computational Pressure-flow Dynamics Derived Fractional Flow Reserve
Authors: LI Kwan Yu , Lam Lok Yee Jane , Leung Ka Lam Calvin , Ren Qingwen , Wu Mei Zhen , Tse Yi Kei Stephanie , Yu Si-Yeung , Li Hang Long , Wong Pui Fai , Yu Shuk Yin , Feng Yundi , Huo Yunlong , Yiu Kai Hang
Published: April 2022

Introduction:
Computational pressure-flow dynamics derived fractional flow reserve (caFFR) has emerged for non-invasive assessment of fractional flow reserve (FFR) in patients with stable coronary artery disease (CAD), without the need for hyperaemic induction and guidewire placement in conventional FFR. The clinical value of caFFR in diabetic patients, who are at risk of microvascular dysfunction, has not been validated. The aim of the study is to evaluate the use of caFFR in diabetic patients with stable CAD.

Methods:
A total of 212 stable CAD patients with diabetes (mean age=67.6±10.6, 66.5% male) were included. Patients were said to be adherent to caFFR if all ischemic vessels, defined by caFFR≤0.8 were treated with PCI and all nonischemic vessels, defined by caFFR>0.8 were not. Otherwise, they were considered to be non-adherent to caFFR. The primary endpoint was 3-year major adverse cardiac events (MACE), defined as a composite of cardiovascular mortality, non-fatal myocardial infarction (MI), stroke and unplanned revascularization.

Results:
Among the 212 patients, PCI was performed in 62.3% of them. A total of 26 composite events occurred, including 5 cardiovascular mortality, 5 non-fatal MI, 2 strokes and 14 unplanned revascularization. The incidence rate of MACE was significantly lower in adherent patients than in non-adherent patients (5.4% vs 15.8%; P=0.01). After multivariate adjustment, adherent patients had a significantly lower risk of MACE than non-adherent patients (adjusted hazard ratio [HR], 0.33; 95% confidence interval [Cl], 0.13-0.83; P=0.02).

Conclusions:
In stable CAD patients with diabetes, caFFR-guided revascularization significantly reduces the risk of MACE in 3 years. The findings support the potential use of caFFR in treatment guidance of diabetic patients.
Abstract 12801: Heart Failure as an Independent Predictor of Insomnia Symptoms
Authors: Gharzeddine Rida , McCarthy Margaret , Yu Gary , Dickson Victoria V
Published: April 2022

Background:
Heart failure (HF) is accompanied with several untoward outcomes including insomnia symptoms. Many factors including comorbidities, experienced symptoms, and psychosocial characteristics associated with HF were attributed to the high prevalence of insomnia symptoms in persons with HF. However, it is not yet clear if HF itself contributes to insomnia symptoms regardless of these associated factors.

Purpose:
The purpose of this analysis was to investigate the association of HF with insomnia symptoms in adjusted models for sociodemographic, clinical, and lifestyle factors.

Methods:
A secondary data analysis guided by the neurocognitive model of insomnia was conducted on data from the health and retirement study using multiple logistic regression. The total sample size included 17,910 subjects of which 1,189 were identified to have HF.

Results:
The results showed that those with HF were approximately two times more likely to have insomnia symptoms (OR:1.95, p <0.001) in the unadjusted model. After adjusting for age, sex, race, ethnicity, education, marital status, income, poverty level, sleep-disordered breathing, obesity, depression symptoms, comorbid diseases, smoking, alcohol consumption, and physical activity using block-wise selection, HF maintained a significant association with insomnia symptoms (OR:1.15, p<0.05). When looking at each insomnia symptom separately, HF significantly predicted difficulty initiating sleep (OR: 1.23, p < 0.01) in the fully adjusted model, but maintained a trend with difficulty maintaining sleep and early morning awakening.

Conclusion:
These results are suggestive of an alerting effect in HF which could be attributed to its pathophysiology. Specifically, the neurohormonal compensatory mechanism and the increased sympathetic stimulation in heart failure may exert an alerting effect during the day and contribute to a hyper-arousal state and difficulty initiating sleep before it partially wears off after sleep. Further studies are needed to investigate this hypothesis.
Abstract 12802: Intron-Mediated Enhancement of
Titin
(
TTN
) Regulates Sarcomere Formation and Function
Authors: Kim Yuri , Kim Seongwon , Neyazi Meraj , Schmid Manuel , Letendre Justin , Ewoldt Jourdan , Xiao Feng , Cloonan Paige , Sharma Arun , Wasson Lauren , Toepfer Christopher , Tai Angela , Gorham Joshua , Oudit Gavin Y , Pu William T , Dickel Diane , Chen Christopher S , Seidman Christine E , Seidman Jonathan
Published: April 2022

Background:
Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure, a major cause of morbidity and mortality. This causality indicates that even two-fold changes in the amount of TTN can profoundly disturb cardiac physiology. Although a critical role of TTN in sarcomere formation and cardiomyocyte contractility is well established, the mechanisms regulating transcription of the
TTN
gene remain poorly understood.

Methods:
We performed bioinformatics analysis to identify a putative transcriptional enhancer of
TTN
. Next, we created biallelic deletion of the enhancer in human induced pluripotent stem cell derived cardiomyocytes and performed enhancer reporter assays both in vitro and in vivo to demonstrate necessity and sufficiency of the enhancer in
TTN
gene expression, respectively. Furthermore, we performed massive parallel reporter assay to define critical transcriptional factors of the TTN enhancer activity and analyzed whole genome sequencing (WGS) data of human patients with unexplained dilated cardiomyopathy (DCM).

Results:
We identified an intron mediated enhancer that promotes cardiac-specific
TTN
expression. Global deletion of this element downregulated
TTN
expression in cardiomyocytes and impaired sarcomere development, while transgenic expression promoted cardiac expression in mice. Using mutational scanning we defined key transcription factor binding sites, including NKX2-5 and MEF2 motifs that promote
TTN
expression in cardiomyocytes. Consistent with these functions, analyses of WGS data in 69 patients with unexplained DCM revealed one rare variant that disrupted the conserved MEF2 transcriptional factor binding motif.

Conclusions:
Discovery of a
TTN
enhancer advances our understanding of cardiomyocyte development, provides an opportunity to modulate
TTN
transcriptional activity, and ultimately develop therapeutic strategies to treat dilated cardiomyopathy caused by TTN haploinsufficiency.
Abstract 12803: Human IPSC-Derived Committed Cardiac Progenitor Cells Engraft and Differentiate Following Transendocardial Injections in a Swine Ischemic Heart Failure Model
Authors: Raval Amish N , Schmuck Eric G , Roy Sushmita , Saito Yukihiro , Zhou Tianhua , Hacker Timothy A , Koonce Chad , Boyer Meghan , Stack Kristin , Hebron Ellen , Nagle Scott , Hsieh Patrick , Kamp Timothy J
Published: April 2022

Introduction:
A hallmark of human myocardium is the inability to regenerate functional myocardium following myocardial infarction (MI) which can result in heart failure. In an effort to remuscularize infarcted myocardium, we tested a novel human iPSC-derived committed cardiac progenitor (CCP) cell population. Whether CCPs survive and differentiate to form grafts following transcatheter delivery in a clinically representative large animal model is unknown.

Hypothesis:
We hypothesized that transendocardial injection (TEI) of CCPs, combined with a cardiac fibroblast-derived matrix (CFM) particles as a cell retention agent leads to functional cardiac tissue grafts.

Methods:
Large MI following coronary artery balloon-occlusion reperfusion was induced in mini-swine that received a 4-drug immunosuppression regimen. 28 days later, TEI targeting the peri-infarct region was performed using combinations of 200 million CCPs with or without 50 mg CFM particles and Flexbumin control. 14 injections/pig were performed, and animals were followed for 4-8 weeks. Histopathology, continuous ECG recording and cardiac MRI were performed.

Results:
Human cell grafts were identified using Ku80+ human cell specific antibody in the initial n=11 evaluable CCP treated swine after 1 month (see representative image, Ku80+ human cells=green). The CCPs largely differentiate into TnI positive cardiomyocytes (red) in grafts observed at one month. Immunolabeling for a panel of cardiomyocyte markers confirmed the presence of human cardiomyocytes. Of n=29 initial pigs, no treatment-related safety issues were identified, such as post TEI pericardial effusion, ventricular tachyarrhythmias or tumors.

Conclusions:
TEI of CCPs, with and without CFM, resulted in grafts of human cardiomyocytes in the myocardium of immunosuppressed pigs, after 1 month post MI. Ongoing cardiac MRI analyses will determine the impact of CCP therapy on cardiac structure and function.
Abstract 12816: Epicardial Adipose Tissue Around the Left Atrium is Associated With Atrial Fibrosis in Patients With Atrial Fibrillation
Authors: Askari-Atapour Bahareh , Kwan Kristen , Anderson Carter A , Jafarvand Mahbod , Birjandian Zeinab , Tregoning Deanna , Boyle Patrick M , Akoum Nazem W
Published: April 2022

Background:
Obesity is a risk factor for atrial fibrillation (AF) and strongly influences the response to treatment. Atrial fibrosis shows similar associations. Left atrial epicardial fat (LAEF) may be a link to these associations.

Objective:
We sought to assess whether LAEF is associated with atrial fibrosis and BMI (Body Mass Index).

Methods:
Patients with atrial fibrillation undergoing catheter ablation were assessed with cardiac MRI for overall epicardial fat, LAEF, and fibrosis quantification. Epicardial fat was imaged using a 3-dimensional Dixon sequence and quantified by contouring regions of fat on axial images (Panel A; Blue regions represent LAEF). Atrial fibrosis was quantified from the Late Gadolinium Enhancement (LGE) MRI. Image registration was used to assess the relationship between left atrial epicardial fat and left atrial fibrosis.

Results:
45 patients underwent the imaging protocol (64±10 years; 76% male). BMI was 29.3±6.1 kg/m
2
, LAEF was 248±155 cm
2
, and LA fibrosis was 17.4±8.4%. LAEF was significantly correlated with both LA fibrosis (Fig B; P=0.017; R
2
=0.125) and BMI (y[BMI] = 0.093x[LAEF] + 5.37; p=0.01, R
2
=0.155). Total epicardial fat was also correlated with BMI (y[BMI] = 0.014x[total epicardial fat] + 9.01; p<0.001, R
2
=0.33). The overlap of LAEF and fibrosis was moderate with a Dice coefficient ranging from 0.26 to 0.49. (Fig C).

Conclusion:
LAEF is associated with obesity (BMI) and LA fibrosis with a moderate degree of colocalization. These findings support a role for LAEF as a contributor to atrial fibrosis and a link between obesity and atrial fibrillation.