bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13792: Association of Immunocompromised State With Coronary Microvascular Dysfunction in Patients With Well-controlled HIV
Authors: Rethy Leah , Kern Joseph , Achenbach Chad , Angarone Michael , Dvorak Stephen , Konstantelos Christopher , PANDIT Jay A , Patel Ravi B , Ryan Juliet , Sinha Arjun , Taiwo Babafemi , Gan Li-ming , Feinstein Matthew J , Shah Sanjiv J
Published: May 2021

Introduction:
Patients with HIV have an elevated risk of cardiovascular disease (CVD) that may be partially driven by inflammation and residual immune dysfunction despite treatment with antiretroviral therapy (ART). Coronary microvascular dysfunction (CMD) is an important pathophysiological link between inflammation, immune dysfunction, and CVD and may provide mechanistic insight into CVD risk among HIV+ patients.

Methods:
We recruited 3 groups of adults aged 40-80 years free of CVD: HIV with evidence of prior/current immunocompromise (n=17), HIV without immunocompromise (n=19), and HIV- controls. All HIV+ participants were on ART and had suppressed viral loads. All controls were on HIV pre-exposure prophylaxis (PrEP). Immunocompromise was defined as nadir CD4 count <200 cells/μL or current CD4 count <500 cells/μL. Participants underwent Doppler echocardiography with coronary flow velocity measurement in the distal left anterior descending coronary artery at rest and during adenosine infusion. CMD was defined as coronary flow reserve (CFR) < 2.50. Multivariable linear regression models assessed the association of HIV group with CFR.

Results:
Of 51 individuals who underwent CFR testing, median (IQR) age was 54 (46-58) and 92% were male. CFR was 3.71 (2.90-4.72) in controls, 3.49 (2.52-4.20) in HIV+/ immunocompromise-, and 2.35 (2.12-2.92) in HIV+/ immunocompromise+ (p=0.002). CMD was present in 7% of controls, 21% of HIV+/immunocompromise-, and 53% of HIV+/immunocompromise+ (p= 0.01). Compared with controls, HIV+/immunocompromise+ was significantly associated with lower CFR after multivariable adjustment (
Table
).

Conclusions:
HIV+ patients with current/prior immunocompromise free of CVD had high prevalence of CMD and had significantly lower CFR compared with controls on PrEP. Future studies should investigate CMD as a possible target for CVD prevention in HIV+ patients, particularly those with a prior or current immunocompromised state.
Abstract 13797: Enabling Advanced Real-world Evidence in Heart Failure: A Pilot Study Defining Preferred Approaches to Electronic Health Record Data Use
Authors: Riskin Dan , Monda Keri L , Dent Ricardo , Garan A. Reshad
Published: May 2021

Introduction:
Real world evidence (RWE) is increasingly used for regulatory and market access decision-making. In heart failure (HF), typical structured datasets have limitations in data accuracy and identifying relevant patient characteristics. Understanding which characteristics require enhancement from unstructured data and how to validly apply extraction methods will improve the definition of complex patient cohorts.

Hypothesis:
Augmenting structured with unstructured electronic health record (EHR) data may overcome challenges in accurately identifying relevant HF patient characteristics.

Methods:
Using EHR data from 4,288 primary care encounters, 20 clinical concepts were defined
a priori
by 3 HF experts. A reference standard was generated through chart abstraction, with each record reviewed by at least two annotators. Inter-rater reliability (IRR) was measured by Cohen’s kappa. EHR structured data (EHR-S) extracted with traditional query techniques and EHR unstructured (EHR-U) data extracted with artificial intelligence (AI) technologies were tested for accuracy against the reference standard.

Results:
In EHR-S, recall ranged from 0-95.1% and precision from 52.9-100%. In EHR-U data processed using AI, recall ranged from 80.4-99.7% and precision from 82.3-100%. Results demonstrated a 45.1% absolute difference and 98.1% relative increase in F1-score (Table). Reference standard IRR was 95.3%.

Conclusions:
RWE credibility and applicability relies on accurate identification of a patient cohort. This study suggests that readily available data sources may not accurately identify patient phenotypes in HF. Novel means of using AI with EHR-U may improve such efforts, particularly for conditions and symptoms. This approach offers a pathway for defining highly accurate HF cohorts that may be useful in studies with narrowly defined or complex phenotypes, such as those where inclusion and exclusion criteria are specific and outcomes require validity.
Abstract 13800: Using Different Scoring Systems to Differentiate In-hospital Mortality in Patients With Extracorporeal Membrane Oxygenation
Authors: Lin Jou W , Hu Nian-Ze , Hsu Jiun , Cheng Hsun-Mao , CHEN Yih-Sharng
Published: May 2021

Introduction:
The objective of this study was to evaluate the performance of different scoring systems in discriminating in-hospital mortality among patients receiving extracorporeal membrane oxygenation (ECMO).

Methods:
This observation registry involved adult patients who received ECMO from 2006 to 2016 in a medical center in Taiwan. Clinical variables collected when ECMO was instituted were used to generate the following scores: Charlson Comorbidity Index (CCI), Acute Physiology and Chronic Health Evaluation (APACHE), sequential organ failure assessment (SOFA) score, the logistic organ dysfunction score (LODS), the multiple organ dysfunction score (MODS), The Simplified Acute Physiology Score III (SAPS3), and the survival after venoarterial ECMO (SAVE) score. A logistic regression model incorporating statistically significant variables was applied to find the predicted probability of in-hospital death, which was then used as a new model-based estimator. Receiver-operating characteristic (ROC) curves were drawn and area under curves (AUC) was used as the marker for discriminatory power.

Results:
A total of 1342 patients (71.5% men) were included with mean age of 53.5 (15.7) years and in-hospital mortality rate 62.3%. Based on the valid observations, the AUCs were 0.590 (95% CI: 0.553~0.627, n = 929) for CCI, 0.672 (95% CI: 0.638~0.706, n = 998) for APACHE, 0.691 (95% CI: 0.655~0.727, n = 841) for SOFA, 0.696 (95% CI: 0.660~0.732, n = 820) for LODS, 0.657 (95% CI: 0.619~0.695, n = 974) for MODS, 0.660 (95% CI: 0.623~0.696, n = 840) for SAPS3, 0.649 (95% CI: 0.596~0.701, n = 429) for SAVE (all p < 0.001), and 0.766 for the model-based estimator (95% CI: 0.740~0.791, n = 1342). When the cases were restricted to the 247 patients in whom all scores could be successfully calculated, the model-based estimator still resulted in the highest discriminatory power (AUC 0.747, 95% CI: 0.686~0.807), with other systems ranging from 0.590 (CCI) to 0.684 (SAPS3).

Conclusions:
The model-based algorithm incorporated mathematically optimized coefficients to produce a new estimator that outperformed different types of clinical risk scores, and could be used for future clinical prediction.
Abstract 13807: Semaglutide Provides More Value for Money Than Dulaglutide or Liraglutide for Prevention of Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease
Authors: Azuri Joseph , Aboalhasan Enis , Hammerman Ariel , Arbel Ronen
Published: May 2021

Introduction:
The Glucagon-Like Peptide-1 receptor agonists (GLP-1a) semaglutide, dulaglutide, and liraglutide reduce major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus
(
T2DM) and established CVD. The American Diabetes Association currently recommends providing GLP-1a therapy to this patient population independently of glycaemic control. Despite proven clinical benefits, providing GLP-1a to all guideline eligible patients is a significant cost burden on healthcare systems. Therefore, it is imperative to compare the value for money of these agents.

Hypothesis:
The newly introduced GLP-1a Semaglutide may be cost-saving compared to dulaglutide and liraglutide for preventing MACE in patients with established CVD and T2DM.

Methods:
We calculated the cost needed to prevent one MACE, by multiplying the annualized number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. We performed a sensitivity analysis to mitigate differences between trial populations and other uncertainties. Drug costs were based on published US prices.

Results:
The cost needed to prevent one MACE with semaglutide is $557,187 ($331,491-$2,194,483) compared to $1,179,360 ($732,888-$2,746,224) with liraglutide and $1,605,904 ($706,044-∞) for dulaglutide. Sensitivity analysis confirmed the advantage of semaglutide.

Conclusions:
Semaglutide prescribed for secondary prevention of MACE in patients with T2DM and established CVD seems to provide more value for money than dulaglutide and liraglutide for the same purpose.
Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction
Authors: Sheng Zejuan , Qiang Xiaoyan , Li Guoyu , Wang Huimin , Dong Wenxin , Wu Frank
Published: May 2021

Introduction:
Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction.

Methods:
Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology.

Results:
TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone.

Conclusions:
TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).
Abstract 13811: The Clinical Significance of End-diastolic Forward Flow on the Prognosis After Pulmonary Valve Replacement in Patients Late After Repair of Tetralogy of Fallot
Authors: Tominaga Yuji , Taira Masaki , Kanaya Tomomitsu , Araki Kanta , Watanabe Takuji , Ueno Takayoshi , Sawa Yoshiki
Published: May 2021

Introduction:
Restrictive right ventricular physiology (r-RVP) is common in late after repair of tetralogy of Fallot (TOF) and reported to reflect diastolic dysfunction. Right ventricular (RV) diastolic dysfunction sometimes remains after pulmonary valve replacement (PVR) and is associated with arrhythmia. Pulmonary arterial end-diastolic forward flow (EDFF) is considered as a marker of r-RVP, and associated with RV volume, right atrial (RA) function, and the degree of pulmonary valve regurgitation (PR). The aim of this study is to evaluate the impact of EDFF before PVR on the clinical outcomes after PVR in patients with repaired TOF.

Methods:
This was a single-center, retrospective review of 46 patients who underwent PVR for moderate to severe PR between 2003 and 2019. Cases were examined EDFF before PVR and divided into two groups: with EDFF (EDFF+, n=23) and without EDFF (EDFF-, n=23). Patients with histories of atrial tachyarrhythmia underwent concomitant maze procedure. RV and RA volume were evaluated by magnetic resonance imaging. Post-PVR survival and the development of arrhythmia were assessed.

Results:
Age at PVR was 38±14 in EDFF+ and 35±10 years old in EDFF- (p=0.41), and the incidence of preoperative arrhythmia was not different (30% and 35%, p=1.0). RVESVI (102±24 and 86±26 ml/m
2
, p=0.048) and RAVI (84±19 and 70±20 ml/m
2
, p=0.025) before PVR, and RVEDVI (116±27 and 100±24 ml/m
2
, p=0.04) and RVESVI (71±23 and 55±16 ml/m
2
, p=0.01) at one year after PVR were greater in EDFF+. One patient in each group died due to non-cardiac disease. 5-year atrial tachyarrhythmia free rate was 62% in EDFF+ and 100% in EDFF- (Log-rank p=0.004). Multivariate Cox regression analysis revealed EDFF before PVR was a risk factor for atrial tachyarrhythmia after PVR (Hazard ratio 17 (95% CI, 2.2-406), p=0.025).

Conclusions:
EDFF before PVR was a significant risk factor for the development of postoperative atrial tachyarrhythmia. EDFF can complement the current indication for PVR.
Abstract 13832: Cardiac Mesenchymal Cells (CMCs) Cultured at Physiologic Oxygen Tension Have Superior Therapeutic Efficacy in Mice With Heart Failure Caused by Myocardial Infarction
Authors: Bolli Robi , Dasari Chandrashekhar , Alkasir Amr , Arshia Asma , Nong Yibing , Guo Yiru , Ashraf Usman , Li Qianhong
Published: May 2021

Stem/progenitor cells are usually cultured at atmospheric O
2
tension (21%); however, since physiologic O
2
tension in the heart is ~5%, using 21% O
2
may cause oxidative stress and toxicity. CMCs, a newly-discovered and promising type of progenitor cells, are effective in improving LV function after myocardial infarction (MI). To determine if 5% O
2
enhances therapeutic efficacy of CMCs, murine CMCs were cultured at 21% or 5% O
2
. Compared with 21% O
2
, culture at 5% O
2
significantly (
P
<0.001) increased cell proliferation, telomerase activity, telomere length, and resistance to severe hypoxia (1% O
2
for 24 h)
in vitro
. Then, LV dysfunction was produced in 48 mice by a 60 min MI; 30 days later, mice received vehicle or CMCs cultured at 21% O
2
or 5% O
2
. After 35 days, the improvement in LV ejection fraction effected by 5% O
2
CMCs was >3 times greater than by 21% O
2
CMCs (5.2 vs. 1.5 units,
P
<0.01) (Figs. A-B). Hemodynamic studies (Millar catheter) yielded similar results both for load-dependent (LV dP/dt) and load-independent (end-systolic elastance) indices (Figs. C-D). Thus, 2 independent methods (echo and hemodynamics) demonstrated that compared with 21% O
2
, using 5% O
2
to culture CMCs results in greater functional improvement in the failing heart. Further, 5% O
2
CMCs produced greater reduction in myocardial fibrosis and exhibited much longer survival after transplantation (
P
<0.01 for both). In conclusion, culturing CMCs at physiologic (5%) O
2
tension results in more rapid proliferation (reducing time and cost to achieve target cell numbers), less senescence, greater resistance to severe hypoxia (making cells better able to survive in scarred regions where O
2
is very low [1-2%]), and superior therapeutic efficacy in promoting cardiac repair after MI. Thus far, almost all preclinical and clinical studies of cell therapy have used 21% O
2
to culture cells. Our data challenge this paradigm and support the need to change the methods used to culture CMCs and possibly other progenitor cells.
Abstract 13836: Long Noncoding Rna Meg3 Protects Against Hepatic Endothelial Senescence in Obesity by Regulating Mitochondrial Function
Authors: CHENG Xiao , Shihabudeen Haider Ali Mohamed Sham , Moran Matthew , Viana Martonio Ponte , Kolape Jaydeep , Schlichte Sarah L , Zimmerman Matthew C , Khalimonchuk Oleh , Feinberg Mark W , Sun Xinghui
Published: May 2021

Introduction:
Long noncoding RNAs (lncRNAs) contribute to the pathogenesis of obesity, a risk factor for cardiovascular disease. The underlying mechanisms are not completely understood, in part, due to that the functions of the majority of them remain unknown in many processes such as mitochondrial homeostasis and cellular senescence. Here, we set out to test the hypothesis that lncRNAs play key roles in obesity by regulating mitochondrial function and cellular senescence in the endothelium.

Methods and Results:
In this study, transcriptome analysis revealed that lncRNA maternally expressed gene 3 (Meg3) is one of the top induced lncRNAs in the endothelium from adipose tissue in diet-induced obese mice. Meg3 knockdown potentiated obesity-induced insulin resistance revealed by intraperitoneal glucose and insulin tolerance tests and an increase in fasting plasma insulin levels (1.67-fold increase; p<0.05); diminished insulin signaling revealed by 43% reduction (p=0.038) in Akt phosphorylation on serine 473 in liver and, to a lesser extent, in skeletal muscle (32%; p<0.05), but not in visceral fat; and increased hepatic endothelial senescence in obese mice (e.g., 2.74- and 3.40-fold increase in p21 and p16 expression, respectively; p<0.001). Endothelial cell-specific p53 knockout partially attenuated Meg3 knockdown-induced cellular senescence and completely restored hepatic insulin signaling in obese mice. Meg3 knockdown inhibited mitochondrial bioenergetics, increased mitochondrial superoxide production, and caused fragmentation of mitochondrial network; also impaired autophagy, induced a type 1 interferon response, and triggered cellular senescence in HUVECs. Finally, the expression of Meg3 is induced in fatty livers of obese patients and strongly correlates with the cellular senescence marker p16 (r=0.50; p=0.0007).

Conclusions:
Deficiency of lncRNA Meg3 contributes to mitochondrial dysfunction, hepatic endothelial senescence, and accelerated obesity-induced insulin resistance. Meg3 induction is important in limiting obesity-induced endothelial senescence and insulin resistance, suggesting that manipulation of Meg3 expression may represent a novel approach to manage obesity-associated cardiometabolic disease.
Abstract 13876: Squat-to-stand Provocation of Dynamic Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy
Authors: Peng Lillian , Newman Darrell B , Geske Jeffrey B
Published: May 2021

Background:
Left ventricular outflow tract (LVOT) obstruction is an important determinant in management of hypertrophic cardiomyopathy (HCM). Valsalva maneuver and amyl nitrite are used in clinical practice during resting echocardiography to induce latent obstruction (LVOT gradient <30 mmHg at rest, ≥30 mmHg with maneuver). With a nationwide shortage of amyl nitrite in 2019, we implemented a “repetitive squat-to-stand” maneuver to provoke LVOT obstruction during echocardiography.

Methods:
Patients with known or suspected HCM without resting obstruction who underwent repetitive squat-to-stand maneuver during echocardiography between February and September 2019 were included. Maximal instantaneous gradients were recorded. Provocable gradients were compared utilizing a two-sided t-test. Amyl nitrite was not available during the study period.

Results:
Squat-to-stand assessments were available in 125 patients without resting obstruction (age 58 ± 15 years, 67% male); 114 also performed Valsalva maneuver. 47 of 125 patients (37.6%) demonstrated provocable obstruction. 46 (36.8%) demonstrated latent obstruction provoked by squat-to-stand, which was severe (gradient ≥50 mmHg) in 29 (23.2%). Of the 46 patients, 19 demonstrated latent obstruction only with squat-to-stand but not with Valsalva, 13 of which demonstrated severe obstruction. Among patients with latent obstruction who performed both Valsalva and squat-to-stand maneuver (n=41), squat-to-stand resulted in a higher gradient than Valsalva maneuver (p<0.0001, Figure).

Conclusion:
Repetitive squat-to-stand maneuver is a clinically useful adjunct to the traditional echocardiographic exam in HCM. This maneuver appears to be more sensitive than the Valsalva maneuver for identifying severe dynamic LVOT obstruction. Use of repetitive squat-to-stand warrants further study in comparison to amyl nitrite, particularly regarding cost savings and diagnostic performance.
Abstract 13907: Patients With NSTEMI Are at Higher Risk, Have Worse Outcomes, but Less Intense Cardiology Follow-up 1-3 Years Post-discharge: Findings From the TIGRIS Registry
Authors: Krishnamurthy Sibi N , Pocock Stuart , Kaul Prashant , Owen Ruth , Chen Jiyan , Goodman Shaun G , Granger Christopher B , Nicolau Jose C , Simon Tabassome , Westermann Dirk , Yasuda Satoshi , Andersson-Sundell Karolina , Brandrup-Wognsen Gunnar , Hunt Phillip , Brieger David , Cohen Mauricio G
Published: May 2021

Introduction:
Non-ST-elevation myocardial infarction (NSTEMI) patients have more comorbidities and extensive CAD than STEMI patients. However, there is a need for comparative data on the long-term prognosis and resource utilization of stable patients after these MI subtypes.

Methods:
TIGRIS enrolled 9027 stable patients 1-3 years post-MI (369 centers, 25 countries) with ≥1 risk factor (age ≥65 years, diabetes, 2nd prior MI, multivessel CAD, CKD). The incidence of cardiovascular (CV) events and deaths, and self-reported EQ-D5 score were recorded over 2 years. Multivariable Poisson regression models were used to compare STEMI and NSTEMI patients for relative risks, adjusting for prognostically relevant patient factors.

Results:
MI subtype was known in 8494 patients (STEMI: 56%; NSTEMI: 44%). At enrollment, NSTEMI patients were more likely to be older, have diabetes, hypertension, hyperlipidemia, and prior CAD compared with STEMI patients. NSTEMI patients had significantly poorer self-rated health and a lower use of dual antiplatelet therapy at discharge and 1-3 years later. NSTEMI patients had a higher incidence of the composite of MI, stroke and CV death over 2 years (5.6% vs 4.0%, p<0.001) and higher all-cause mortality (4.1% vs 2.6%, p<0.001) vs STEMI patients (Figure). These excess risks for the composite outcome attenuated after adjusting for baseline characteristics (adj RR 1.18, 95% CI 0.96-1.45, p=0.11), but remained significant for all-cause mortality (adj RR 1.31, 95% CI 1.02-1.68, p=0.03). Resource utilization over 2 years was higher in NSTEMI patients, although the mean number of cardiologist visits were higher for STEMI patients (4.2 vs 2.8, p<0.001).

Conclusions:
NSTEMI patients had a less favorable risk profile and experienced more adverse CV events during long-term follow-up than STEMI patients, but had less intense cardiology follow-up. Continued efforts are needed to optimize secondary prevention and care of stable patients after NSTEMI.
Abstract 13911: Interleukin-5-induced Eosinophil Population Improves Cardiac Function After Myocardial Infarction
Authors: Xu Jun-Yan , Jiang Wen-Yang , Xiong Yu-Yan , Tang Rui-Jie , Ning Yu , Yang Yue-Jin
Published: May 2021

Background:
Eosinophils have been commonly recognized as one of the major participants in helminth infection and allergic diseases. Recent studies suggest that these innate immune cells mediate tissue repairs after muscle, hepatic, or endometrial injuries. Yet, the precise role of eosinophils in myocardial infarction (MI) remains unclear. Interleukin (IL)-5 is the most important cytokines that are responsible for the development, activation, and survival of eosinophils. Here, we report a role of IL-5 in infarcted heart.

Methods and Results:
MI was induced by permanent ligation of left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot show that infarcted heart IL-5 expression is increased by 2.35-fold (P<0.01) higher than their expression in the heart of sham mice at day 5 after surgery. External supply of recombinant mouse IL-5 (100 μg/kg/day for 3 days) reduces the infarct size (by 13.38%, P<0.01), increases ejection fraction (from 32.41% to 43.93%, P<0.01), and increases angiogenesis (CD31 area from 3.35% to 4.14%, P=0.03) in the peri-infarct zone. An expansion of eosinophils is observed in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of eosinophils by TRFK5 pretreatment mutes the beneficial effects of IL-5 in MI mice. Mechanistic studies also demonstrate that IL-5 increases the accumulation of M2 macrophages in infarcted myocardium at day 7 post-MI.
In vitro
co-culture experiments reveal that eosinophils shift bone marrow-derived macrophage polarization towards the M2 phenotypes. This effect is abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses show that eosinophils promote the macrophage downstream STAT6 phosphorylation.

Conclusions:
We demonstrate here that IL-5 facilitates the recovery of post-MI cardiac function by promoting eosinophils accumulation and subsequent polarization of M2 macrophages via the IL-4/STAT6 axis.
Abstract 13912: 17-Beta-Estradiol Directly Regulates Microtubule Dynamics: New Insights Into Sex-Differences in Right Ventricular Function in Pulmonary Hypertension
Authors: Prisco Sasha Z , Xiong Ping Y , Goldblum Rebecca , Potus Francois , Martinez Algarin Kenneth , Rose Lauren , Thenappan Thenappan , Gardner Melissa K , Archer Stephen L , Prins Kurt W
Published: May 2021

Introduction:
Female sex is associated with better right ventricular (RV) function in pulmonary hypertension (PH). The female sex hormone 17-beta-estradiol is postulated to mediate these differences, but the molecular mechanisms underlying these observations are incompletely defined. Interestingly, 17-beta-estradiol induces microtubule depolymerization in cell culture, which may be relevant to RV dysfunction because microtubule remodeling promotes RV dysfunction via dysregulation of junctophilin-2 (MT-JPH2 pathway). We speculate that 17-beta-estradiol modulates the MT-JPH2 pathway and preserves RV function in PH.

Methods:
Pressure-volume assessments quantified RV function in monocrotaline (MCT) and pulmonary artery-banded (PAB) rats. Immunoblots quantified the tubulin and junctophilin-2 protein content in RV extracts. Echocardiography quantified RV function by RV fractional area change for 379 human PH patients. Sedimentation experiments, fluorescence-based polymerization assessments, and total internal reflection fluorescence (TIRF) microscopy examined the effects of 17-beta-estradiol on microtubules.

Results:
Female sex results in better RV function and less dysregulation of the MT-JPH2 pathway in both MCT and PAB rats. Moreover, in human PH, female sex was associated with better RV function, which persisted after adjusting for afterload. 17-beta-estradiol inhibited microtubule polymerization in vitro and TIRF microscopy showed 17-beta-estradiol localized to microtubule tips and prevented further microtubule polymerization.

Conclusions:
Preclinical and human studies show that females are better able to tolerate RV pressure overload. There are blunted microtubule-mediated t-tubule remodeling and preserved RV function in female MCT and PAB rats. In human PH, females have better RV function. These findings may be due to 17-beta-estradiol directly regulating microtubule dynamics as shown by sedimentation and polymerization assays and TIRF microscopy. These results provide additional insights into sex-differences in RV function in PH.
Abstract 13920: Improved Outcome Prediction Modelling in Neonatal Congenital Heart Disease With Metabolomic Feature Clustering
Authors: Heibel Jessica J , Graham Eric M , Roux Aurelie , Graham David , Manlhiot Cedric , Everett Allen D
Published: May 2021

Introduction:
Neonatal heart surgery requiring cardiopulmonary bypass (CPB) is associated with significant morbidity and mortality. Methods to improve outcome prediction are lacking.

Hypothesis:
Targeted metabolic profiling can identify critical metabolites associated with important post-operative clinical outcomes. These in turn could be integrated into clinical prediction models.

Methods:
Secondary analysis of serum samples from the neonatal congenital cardiac surgery with CPB methylprednisolone trial, which evaluated effects of steroids on outcomes. Samples were from pre-op, immediate post-CPB, and 12 hrs post op. Outcomes were a cardiac dysfunction composite (death, ECMO, cardiac arrest and lactate) and low cardiac output syndrome (LCOS). Metabolite levels were determined with targeted mass spectrometry (LC/MS/MS). Principal component (PC) analysis and multivariable regression analysis with bootstrapping were used to assess the association between metabolic profiles and outcomes.

Results:
Total cohort had 149 patients. PC analysis identified 6 PCs (PC1-PC6) that explained 51% of variance. When PCs and metabolites were added to a base clinical model, model fit for the cardiac dysfunction composite outcome was significantly improved (c-stat 0.819 vs 0.902, p<0.001) as well as LCOS (c-stat 0.576 vs. 0.803, p=0.76 vs. p=0.01). Using adjusted regression models, metabolites (some of which are included in PCs) significantly associated with cardiac dysfunction composite outcome were proline (p=0.004) and leucine (p=0.01). Metabolites associated with LCOS were n-acetyltryptophan (p=0.01), glycocholic acid (p=0.001), cortisol (p=0.02), nicotinamide (p=0.04), methyladenosine (p=0.01) and methionine (p=0.01). For cardiac composite outcome, cumulative and post op values were significant, whereas all time points were for LCOS.

Conclusions:
Combining metabolic profiles with patient characteristics revealed significant pre-op metabolites associated with important clinical outcomes. Given that the association held true for all time points, these observations could be used to design molecular signature for post-operative cardiac complications or, to create prediction models based on pre-operative metabolic profiles.
Abstract 13944: Biracial Proteomic Profiling Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Individuals
Authors: Katz Daniel H , Tahir Usman A , Ngo Debby , Benson Mark , Gao Yan , shi xu , Nayor Matthew G , Keyes Michelle J , Larson Martin G , Hall Michael E , Correa Adolfo , Sinha Sumita , Shen Dongxiao , Herzig Matthew , Yang Qiong , ROBBINS Jeremy M , Chen Zsu-Zsu , Cruz Daniel E , Peterson Bennet , Ramachandran Vasan S , Wang Thomas J , GERSZTEN Robert E
Published: May 2021

Background:
Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and compared it to a white cohort.

Methods:
We measured 1305 plasma proteins using an aptamer-based proteomic platform (SOMAscan™) in 1772 black participants in the Jackson Heart Study (JHS) with available baseline LV mass as assessed by 2D echocardiography, as well as 1600 free of HF with follow-up assessment of incident cases. Mean follow-up time was 11 years; 152 cases of incident HF hospitalization were identified. Models were adjusted for age, sex, body mass index, estimated glomerular filtration rate (as calculated by CKD-EPI equation), systolic blood pressure, hypertension treatment, presence of diabetes, total/HDL cholesterol, prevalent coronary disease, and current smoking status. Incident HF models were also adjusted for incident coronary heart disease. We then compared protein associations in JHS to those observed in whites from the Framingham Heart Study (FHS) to examine significant differences.

Results:
In JHS, there were 112 proteins associated with LV mass and 10 proteins associated with incident HF hospitalization with FDR <5%. Several proteins showed expected associations with both LV mass and HF, including N-terminal pro-BNP (β = 0.04 [0.02, 0.05], p = 1.0 x 10
-8
, HR = 1.46 [1.20, 1.79], p = 0.0002). The strongest association with LV mass was more novel: leukotriene A4 hydrolase (LKHA4) (β = 0.05 [0.04, 0.06], p = 2.6 x 10
-15
). Conversely, Fractalkine/CX3CL1 showed a novel association with incident HF (HR = 1.32 [1.14, 1.54], p = 0.0003). While proteins like Cystatin C and N-terminal pro-BNP showed consistent effects in FHS, LKHA4 and Fractalkine were significantly different.

Conclusions:
We identify several novel biological pathways specific to black individuals hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and Fractalkine. Further studies are needed to validate these results and elucidate the detailed underlying mechanisms.
Abstract 14042: Weight Loss Favorably Impacts Left Ventricular Mass and Wall Thickness by CMR and CT in Patients With Hypertrophic Cardiomyopathy: A Retrospective Case Series
Authors: DeFonte Maria , Goldstein Jonathan , Massera Daniele , Stepanovic Alexandra , Gee Alexander , Latson Larry , AXEL Leon , Sherrid Mark
Published: May 2021

Introduction:
Hypertrophic Cardiomyopathy (HCM) is a relatively common inherited heart disease with variable phenotypic expression. While pathogenic variants in sarcomeric genes are considered responsible for the development of left ventricular (LV) hypertrophy, environmental modulation of phenotype may explain the known heterogeneity. Obesity is common in HCM patients and is associated with increased LV mass in the general population.

Hypothesis:
We hypothesized that weight loss in obese patients with HCM would be associated with a decrease in LV mass and maximal wall thickness.

Methods:
Patients with HCM who achieved therapeutic weight loss and underwent cardiac MRI (CMR) or computed tomography (CT) before and afterwards were included. Standard LV measurements including wall thickness in an 18-segment model were performed blindly with respect to name, time and BMI for un-biased comparison.

Results:
We included 6 patients (2 female, age 55 ± 6.5 years, baseline BMI = 36.7 ± 5.2 kg/m
2
) who achieved 16.3 ± 10.8 kg weight loss after 35 ± 12 months with diet and exercise (n=4) or bariatric surgery (n=2). After weight loss, we observed a mean proportional decrease in total LV mass of 25 ± 16% (p=0.004), and a 19 ± 7% decrease in indexed LV mass (p=0.007). Furthermore, there was a numerical decrease in mean wall thickness in 14 out of 18 LV segments measured; 9 segments had more than a 10% decrease. The most noticeable changes were at the basal inferolateral wall (25 ± 13% decrease) and basal inferoseptum (19 ± 18%) decrease (Table).

Conclusions:
In this series of patients with HCM, weight loss favorably affected LV mass and wall thickness. Further research is needed to explore the impact of weight loss on HCM phenotypic expression and symptoms.
Abstract 14047: Novel Noninvasive Risk Stratification Method Using Control-and-stability-theory Applied to 12-lead-ECG Repolarization Patterns in Brugada Type1 Subjects
Authors: Sabatini Antonella
Published: May 2021

Background:
Brugada syndrome (BrS) risk stratification in asymptomatic subjects and its underlying pathophysiological dynamics is complex.

Purpose:
This study aims to analyze, from alternative standpoints, superficial 12-lead ECG V2 repolarization patterns (repol.). This method diverges from ECG pattern characterization (patterns, angles, shapes, intervals, waves); it rather exploits nonlinear dynamics and stability of ECG repol. to assess stability driving cardiac dynamics: basal, after flecainide, during RF ablation, after 2nd flecainide test and post procedure.

Target:
to lower the number of invasive electrophysiology studies, furthering knowledge and applications of control-and-stability-theory applied to ECG.

Methods:
A stability control closed loop system has been designed to model electrophysiology dynamics of cardiac conduction: ECG segments being the input-output of the system. (Figure). A sequence of V2 repol. have been scanned, digitized and quantitatively processed yielding stability parameters (poles in S-plane). Scanning by Digitizeit - Digital River GmbH. S-plane computation by Microsoft Office, Wolfram Demonstrations Project & Contributors, https://demonstrations.wolfram.com

Results:
Figure.

Conclusions:
Based on our data, 1) 12-lead-ECG repol. are associated with increasing stability (parameter values b), denoting underlying nonlinear dynamics, trending to incremental stability from basal to end of procedure.2) The incremental stability associated with all the process phases, from basal to end of procedure, indicates a potential use of this methodology to BrS risk stratification. Unstable repol. may be classified as high VT risk.

In conclusion, furthering control-and-stability-theory applied to 12-lead ECGs aims to deeper comprehension of physiological and pathological substrates of malignant arrhythmias, and to focus on noninvasive risk stratification strategies for ICD implantation indication in BrS.
Abstract 14203: Secondary Sarcopenia Assessed by Computed Tomography Can Predict Hospitalization for Heart Failure in Adults With Fontan Circulation
Authors: Shiina Yumi , Nagao Michinobu , Inai Kei
Published: May 2021

Introduction:
Sarcopenia is one of the important predictors of heart failure (HF) in patients with cardiac problems.

Hypothesis:
Skeletal muscle pump is very important to maintain Fontan circulation. We aimed to quantify the volume of the psoas major muscle (PMM) and investigate whether it is relevant to HF hospitalization in adults with Fontan circulation.

Methods:
A total of 154 adults with Fontan circulation, and 30 age-matched adults were studied retrospectively. We identified secondary sarcopenia by measuring the PMM volume, using non-contrast abdominal computed tomography (CT).

Results:
PMM indexed volume in Fontan patients was lower than controls (206.4+/-18.0 cc/m2 vs 288.0+/-61.1 cc/m2, P<0.0001). In Fontan men, PMM indexed volume correlated with New York Heart Association functional class (NYHA FC). PMM indexed volume in Fontan women correlated with age, NYHA FC, and serum creatinine. Using a multivariate Cox hazards analysis, NYHA FC ≧3 was an important prediction of hospitalization due to HF in Fontan men. In Fontan women, NYHA FC ≧3, brain natriuretic peptide (BNP), PMM indexed volume, and protein losing enteropathy (PLE) were important predictions of hospitalization due to HF. Among all Fontan patients, those with low PMM volumes had a poorer prognosis in HF (Log rank P=0.012 [men] and 0.0009 [women]).

Conclusions:
PMM volume reduction has an adjunctive prediction of HF hospitalization in adults with Fontan circulation, particularly in Fontan females. Secondary sarcopenia may have a negative impact on the prognosis of HF in this population. The assessment of skeletal muscle mass also may be a comprehensive screening tool for multi-organ dysfunction in Fontan circulation.
Abstract 14207: Endothelial Progenitor Cells, T Cells and Macrophages’ Peripheral Levels as Possible Predictive Biomarkers of Acute Myocardial Infarction
Authors: Salybekov Amankeldi A , Sakai Katsuaki , Natsumeda Makoto , Vorateera Kosit , Ikari Yuji , Asahara Takayuki
Published: May 2021

Introduction:
Acute myocardial infarcted (AMI) patient prognosis is strictly dependent on early diagnosis and the adoption of adequate interventions.

Hypothesis:
Immune cells' blood level as a possible candidate to use distinct diagnostic biomarkers of AMI (H1) with/out the combination with clinical-laboratory findings are little known (H2).

Materials &Methods:
Eighteen patients with the diagnosis of AMI were enrolled. Patients with a history of chronic inflammatory disease excluded. All patients underwent emergent percutaneous coronary intervention via the radial artery and guided by optical coherence tomography. Peripheral blood was drawn after obtaining informed consent from patients at days three and seven (MI-D3 & MI-D7) after onset AMI along with sixteen healthy volunteers as a control. The mononuclear cells isolated by density gradient centrifugation and evaluated with EPCs colony formation assay, and flow cytometry analysis (FCA).

Results:
FCA revealed that total mononuclear live cells were significantly lower at MI-D3 and MI-D7 in myocardial infarcted patients compared with healthy controls (55.18±6.7 vs. 77.5±2, P>0.01; and 64.52±7.33 vs. 77.5±2, P>0.08, respectively). An area under the ROC curve (AUC) in MI-D3 was 0.95 (P>0.0007), that is, total CD34+cells/ml counts for MI-D3 vs. healthy controls whereas at MI-D7 the value of EPCs as a predictor was reduced AUC=0.71(P<0.16). In correlation analysis, coronary vessels lesions number inversely correlates vs. MI-D3 total EPCs number (r= -0.45) but not at MI-D7 (r= 0.39). Correlation test showed the tendency of a positive correlation between creatine kinase myocardial band to CD8+ cells at MI-D3 (r=0.58; P<0.054) but not at MI-D7. ROC curve analysis depicted a high accuracy AMI prediction rate of CD8+ cells at MI-D3 (AUC=0.94; P>0.0004) and MI-D7 (AUC=0.85; P>0.03). Notably, all T cells subsets negatively correlated with myeloid cell subsets such as M1 and M2 macrophages at MI-D7, indicating T cells loss in PB stream compensated by monocyte/macrophage.

Conclusion:
Our data demonstrated that circulating EPCs number associates with cardiac vessel lesion, whereas CD8+ cells may serve as a high accuracy biomarker of AMI with a combination of classical clinical-laboratory findings.
Abstract 14210: Comparison of Two Recent Ceramide-based Coronary Risk Prediction Scores: CERT and CERT-2
Authors: Leiherer Andreas , Muendlein Axel , Saely Christoph H , Laaksonen Reijo , Laaperi Mitja , Vonbank Alexander , Fraunberger Peter , Drexel Heinz
Published: May 2021

Introduction:
The Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses circulating ceramide concentrations to allocate patients into one of four risk categories. This test has recently been updated (CERT-2), now additionally including phosphatidylcholine concentrations.

Hypothesis:
We hypothesize that CERT and CERT-2 have the power to predict cardiovascular mortality in patients with cardiovascular disease (CVD).

Methods:
We investigated a patient cohort of 999 patients with established CVD.

Results:
Overall, comparing survival curves (figure) for over 12 years of follow up and the predictive power of survival models using net reclassification improvement (NRI), CERT-2 was the best predictor of cardiovascular mortality, surpassing CERT (NRI=0.456; p=0.01) and also the 2019 ESC-SCORE (NRI=0.163; p=0.04). Patients in the highest risk category of CERT as compared to the lowest category had a HR of 3.63 [2.09-6.30] for cardiovascular death; for CERT-2 the corresponding HR was 6.02 [2.47-14.64]. Among patients with T2DM (n=322), the HR for cardiovascular death was 3.00 [1.44-6.23] using CERT and 7.06 [1.64-30.50] using CERT-2; the corresponding HRs among non-diabetic subjects were 2.99 [1.20-7.46] and 3.43 [1.03-11.43], respectively.

Conclusions:
We conclude that both, CERT and CERT-2 scores are powerful predictors of cardiovascular mortality in CVD patients, especially in those patients with T2D, performance is even higher with CERT-2.
Abstract 14215: Cognitive Impairment in Adult Congenital Heart Disease Survivors: A Pilot Study
Authors: Rodriguez Monserrate Carla P , Jakkam Rajeshwari , Clay Emily , Gauvreau Kimberlee , GURVITZ Michelle Z
Published: May 2021

Introduction:
The most common comorbidities in children with congenital heart disease (CHD) are neurodevelopmental and psychosocial impairments, particularly in areas of executive function, memory, attention, and behavioral control. Limited studies in the adult CHD population suggest similar impairments exist and adults with CHD may be at increased risk for dementia. No studies have screened specifically for mild cognitive impairment and dementia in adult CHD patients.

Methods:
We performed a prospective cross-sectional study of adult CHD patients, ages 30-65 years, who were coming for routine clinic visits. We administered the Mini-Mental State Exam (MMSE) and scores were compared with population norms adjusted by age and education level. We also evaluated the association of MMSE scores with CHD complexity, demographic and clinical risk factors.

Results:
A total of 125 patients were recruited (55% male). The median age was 40 years (range 30-65). Almost all participants (97%) had a high school degree and 75% had some college education or advanced degrees. The majority of patients (94%) had moderate or complex CHD. Adjusting for age and education, CHD participants scored significantly lower than the general population (median 1 point lower, p=0.001). The greatest impairments occurred in recall and orientation. Factors associated with lower scores included decreased systemic ventricular function (p=0.028) and having ≥2 cardiac catheterizations (p=0.006). Five percent of the total cohort met the general threshold for mild cognitive impairment (MMSE<24). Clinical factors associated with this degree of cognitive impairment were duration of cyanosis (p=0.005) and decreased systemic ventricular function (p=0.003).

Conclusions:
Our pilot study showed that, when adjusted for age and education level, adult CHD patients had significantly lower MMSE scores than the general population, with 5% meeting criteria for mild cognitive impairment. These findings suggest that subtle and early neurodevelopmental changes are present in the adult CHD population. Further studies are needed to investigate those changes and evaluate potential disease modifying therapies that might influence long-term outcomes in the adult CHD population.
Abstract 14239: Risk Factors for One-year Mortality and Allograft Loss in Pediatric Heart Transplant Patients Using Machine Learning: Analysis of the Pediatric Heart Transplant Society Database
Authors: Wisotzkey Bethany L , Asante-Korang Alfred , Kirklin James K , Cantor Ryan , Koehl Devin , Jaeger Byron , Thrush Phillip , Mantell Benjamin , Everitt Melanie D , Brickler Molly , Kuhn Micheal A
Published: May 2021

Background:
Pediatric heart transplant (TX) patients are at greatest risk of graft loss (GL) in the first year, which may increase due to accumulated risks in the pre-TX period. Machine learning (ML) may identify clinically relevant outcome characteristics without prior statistical assumptions. We assessed whether ML could improve risk assessment for one-year patient or graft survival in pediatric heart TX.

Methods:
Patients in the PHTS database from January 2010 to December 2016 and January 2017 to June 2019 were included in training (TRN) and testing (TST) sets, respectively. Primary outcome was time until death, GL, or censoring. Using TRN, we selected the 12 most important recipient predictors based on contributions to model fit by applying boosted decision trees. Proportional hazards, boosting, and oblique random survival forest models were developed using these predictors. Discrimination and calibration were compared at 1 year post-TX using TST. The contribution of each predictor to patient’s predicted log-hazard was estimated using SHapley Additive exPansion (SHAP) values.

Results:
TRN (N=2,686) included 1,368 (51%) patients with cardiomyopathy (CM), 1,247 (46%) with congenital heart disease (CHD), and 71 (2%) other. TST (N=1,101) included 509 (46%) with CM, 569 (52%) with CHD, and 23 (2.1%) other. Incidence of GL or death (95% CI) in TRN and TST was 8.13 (7.07, 9.25) and 9.04 (6.93, 11.3) events/100 person years. Among the three models fitted to TRN, boosting obtained the highest concordance index at 1-year post-TX in TST, 0.752 (95% CI 0.695-0.810), and exhibited no evidence of miscalibration. Primary diagnosis of non-CM was the strongest predictor according to the boosting model (mean SHAP 0.398), followed by cardiopulmonary bypass time (mean SHAP 0.308);(
Figure 1
).

Conclusions:
ML can identify salient predictor variables and develop generalizable risk prediction equations using data from pediatric TX patients and may improve patient selection.