bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19274: Coronary Artery Ectasia Are Frequently Observed in Patients With Bicuspid Aortic Valves With and Without Aneurysm of the Ascending Aorta
Authors: Meindl Christine , Achatz Birgit , Huber Deborah , Hubauer Ute , Buchner Stefan , Debl Kurt , Fenk Sabine , Strack Christina , Hengstenberg Christian , Schunkert Heribert , Meisinger Christa , Maier Lars , Baessler Andrea , Fischer Marcus
Published: July 2021

Background:
The exact etiology and prognostic significance of coronary artery ectasia (CAE) is still unknown. The presence of CAE is influenced by genetic factors and related to the presence of aneurysms in other vascular beds. Bicuspid aortic valve (BAV) disease is frequently accompanied by ascending aortic aneurysm. Since the aortic valve, the ascending aorta, and the proximal parts of the coronary arteries share a common embryonic origin, we hypothesized that CAE is associated with BAV disease.

Methods:
181 patients with suspected aortic valve disease (n=101 BAV) underwent both cardiac magnetic resonance (CMR) imaging and coronary angiography. Eighty subjects with tricuspid aortic valve (TAV) disease were similarly studied and served as controls. The readers of the angiograms were blinded to valve type and clinical data. In order to confirm the association of CAE with BAV, the frequency of CAE was evaluated in an in-house BAV registry (n=500) and compared to the frequency of CAE in the German MI family study, in which the heritability of CAE was formerly established (899 with available coronary angiograms), as well as in an observational registry of “real-life patients” undergoing coronary angiography for clinically indicated reasons (n=3471). Furthermore the frequency of CAE was investigated in a subgroup of the KORA MI study, which is a population-based registry that comprises all hospitalized cases of acute non-fatal MI and coronary deaths occurring in inhabitants of a defined study region (n=403).

Results:
Compared to TAV disease, CAE occured twice as frequently in CMR confirmed BAV disease, (17.5% vs. 41.6%, p=0.0005). Ascending aortic aneurysm or ectasia was diagnosed in 60 subjects with BAV disease (59.4%), but CAE occurred similarly between subjects with (59.5%) and without (40.5%) ascending aortic pathology. The common appearance of CAE in patients with BAV could be independently confirmed in the BAV registry (38.9%), whereas CAE was found less frequently in family history positive MI patients (21.2%), and rarely in unrelated “real-life” catheterization patients (5.2%).

Conclusion:
To our knowledge, our data show for the first time that ectatic coronary artery disease is a common appearance of BAV disease with and without ascending aortic aneurysm.
Abstract 19314: Impact of Body Mass Index on Clinical Outcomes in Complex Adult Congenital Heart Disease
Authors: Toh Norihisa , Uribe Morales Ines , Albinmousa Zakariya , Saifullah Tariq , Hatton Rachael , Nair Krishnakumar , Wald Rachel , Roche S. Lucy
Published: July 2021

Background:
Obesity can adversely affect most organ systems and increases the risk of comorbidities likely to be of consequence for patients with complex adult congenital heart disease (ACHD). Conversely, several studies have demonstrated that low body mass index (BMI) is a risk factor for heart failure and adverse outcomes after cardiac surgery. However, there are currently no data regarding the impact of BMI in ACHD.

Methods:
We examined the charts of 87 randomly selected, complex ACHD patients whose first visit to our institution was at 18-22 years old. Patients were categorized according to BMI at initial visit: underweight (BMI < 18.5 kg/m
2
), normal (BMI 18.5 - 24.9 kg/m
2
), overweight/obese (BMI ≥ 25 kg/m
2
). Events occurring during follow-up were recorded. Data was censured on 1/1/2014. Cardiac events were defined as a composite of cardiac death, heart transplantation or admission for heart failure.

Results:
The cohort included patients with the following diagnoses: tetralogy of Fallot n=31, Mustard n=28, Fontan n=17, ccTGA n=9 and aortic coarctation n=2. The median (IQR) duration of follow-up was 8.7 (4.2 - 1.8) years. See table for distribution and outcomes by BMI category. Cardiac events occurred in 17/87 patients. After adjustment for age, sex, and underlying disease, the underweight group had increased risk of cardiac events (HR=12.9, 95% CI: 2.8-61.5, p < 0.05). Kaplan-Meier curves demonstrate the poorer prognosis of underweight patients (Figure).

Conclusions:
Underweight was associated with increased risk of late cardiac events in ACHD patients. We were unable to demonstrate significant overweight/obesity impact.
Abstract 19328: Clinical Predictors of Renal Failure in Heart Transplant Patients Following Initiation of Calcineurin Inhibitor Free Regimen
Authors: Elboudwarej Omeed , Patel Jignesh , Kittleson Michelle , Liou Frank , Kobashigawa Jon
Published: July 2021

Purpose:
Calcineurin inhibitor (CNI) therapy has been the cornerstone of standard triple-drug immunosuppressive therapy that has significantly improved outcomes after heart transplantation (HTx). However, CNI-induced nephrotoxicity remains a significant cause of morbidity and mortality. Renal-sparing protocols (RSP) using CNI-free regimens have improved renal function in some patients (pts). The clinical variables associated with development of renal failure despite RSP initiation are unknown. We therefore evaluated HTx pts on RSP for possible risk factors associated with renal failure.

Methods:
Of 1,424 HTx pts between 1/1994 to 1/2011, 61 were identified who underwent RSP. Creatinine values were obtained at time of RSP initiation and ≥3 months post-RSP. The CKD-EPI Cr Equation (2009) was used to estimate GFR. We assessed pts for type of CNI, prednisone use, ACE-inhibitor/ARB use, calcium-channel blocker use, sex, race, hypertension, diabetes mellitus, obesity, and hypercholesterolemia. A logistic regression model was used to determine if there was an association between the clinical variables measured and stage IV renal failure (estimated GFR <30 mL/kg/m2).

Results:
40 patients (66%) developed renal failure at an average of 14.4 ± 12.8 months after initiating RSP. Pts with an estimated GFR <30 mL/kg/ m2 at time of RSP initiation had a 5.4-fold (1.69-17.26, p=0.004) higher risk of developing renal failure. By multivariate logistic regression, this relationship remained significant after controlling for potential confounders in the relationship between RSP and renal failure, with a 8.9-fold (1.64-48.4; p=0.01) risk of renal failure in pts with an estimated GFR <30 mL/kg/ m2 at time of RSP initiation. The other clinical variables tested did not significantly affect outcome (Table).

Conclusions:
RSP does not appear to be effective in pts with advanced renal disease. RSP should be considered in pts with CNI nephrotoxicity at an earlier stage of the disease.
Abstract 19362: Bridging the Gap Between Functional and Biological Phenotypes in Pediatric Pulmonary Hypertension
Authors: Kheyfets Vitaly O , Dunning Jamie , Dunbar Ivy , Hunter Kendall , Troung Uyen , Shandas Robin
Published: July 2021

Introduction:
Pediatric Pulmonary Hypertension (PH) is a degenerative disease that ultimately leads to Right Ventricular (RV) dysfunction. RV functional and biological (e.g. N-Terminal proB-type Natriuretic Peptide, NT-proBNP) phenotypes can provide insight into performance and ventricular distress, respectively. Nevertheless, they are normally considered independently, and should be associated to paint a more comprehensive picture of the cardio-pulmonary system. The most utilized prognostic metric of RV performance is Cardiac Output (CO), as it gives a direct measure of the ventricle’s “pumping” ability. CO is only indicative of the immediate functional state and lacks any predictive or stratification value. RV-Pulmonary Artery (PA) axis decoupling (VVC = RV end-systolic elastance/arterial elastance) represents a decrease in the RV functional reserve, and therefore an inability to accommodate an increase in afterload. Therefore, it is more comprehensive of the entire cardio-pulmonary system than CO.

Hypothesis:
RV-PA coupling is better associated with NT-proBNP than Cardiac Index (CI = CO/Body Surface Area).

Methods:
26 pediatric PH patients underwent Right Heart Catheterization (RHC), an echocardiograph, and blood composition diagnostics. A 0-D model (Fig. 1a) of the comprehensive cardio-pulmonary system, incorporating extensive patient specificity, was developed to estimate RV pressure-volume curves under baseline and challenged conditions, and approximate the VVC ratio.

Results:
CI was not found to be statistically associated with NT-proBNP (Fig. 1b). Nevertheless, VVC was found to be non-linearly related to NT-proBNP expression (Fig. 1c), thus
rejecting the null hypothesis
.

Conclusion:
NT-proBNP is a biomarker of RV-PA functional decoupling. Considering the inter-compartmental interaction of the entire cardio-pulmonary system offers a better picture of PH disease progression then assessing RV “pump” performance.
Abstract 19504: Factors Predicting Sinus Rhythm in Patients Cardioverted in the X-VERT Study
Authors: Ezekowitz Michael D , Cappato Riccardo , Klein Allan , Ming Isabelle L , Hemmrich Melanie , van Eickels Martin , Hohnloser Stefan H
Published: July 2021

Introduction:
The X-VERT trial is the first large, prospective study of a novel oral anticoagulant in patients undergoing elective cardioversion. Patients were randomized to rivaroxaban (20mg or 15mg once daily if the CrCl was between 30 and 49 ml/min) or Vitamin K antagonist (VKA) at a ratio of 2:1. Patients were assigned to an early or delayed cardioversion strategy per the local investigator’s judgment.

Aim:
To determine factors predictive of sustained sinus rhythm at the end of treatment (i.e. 6 weeks) after cardioversion.

Methods:
Patients with non-valvular AF of >48 h or unknown duration were randomized. Univariate and multivariate analysis of logistic regressions were performed to detect potential predictors of clinically relevant variables.

Results:
A total of 1504 randomized patients were scheduled for either early (872 patients, 58%) or delayed (632 patients, 42%) cardioversion. 1398/1504 (93%) patients underwent cardioversion (electrical or pharmacological) or experienced spontaneous cardioversion during the treatment period. The time intervals from randomization to their first cardioversion (electrical n=1,253, pharmacological n=29 or spontaneous n=116) were 2.7 ± 2.8 days versus 27.9 ± 10.1 days for early versus delayed cardioversion. The acute success of their first cardioversion (electrical or pharmacological) was seen in 1107/1282 (86.3%) patients. At the end of treatment visit, 794/1504 (52.8%) patients were in sinus rhythm. In the multivariate analysis early cardioversion was a strong predictor of sustained sinus rhythm (p<0.01).

Conclusions:
In X-VERT, early cardioversion was predictive of sustained sinus rhythm. Shorter duration AF correlated with sinus rhythm.
Abstract 19515: Statin Use is Associated with Reduced All-Cause Mortality Following Bioprosthetic Heart Valve Implantation
Authors: Albaghdadi Mazen S , Andrei Adin-Christian , Li Zhi , Kruse Jane , McDonald Eileen , Bonow Robert , McCarthy Patrick
Published: July 2021

Objective:
This study examined the impact of statin use on clinical outcomes in patients undergoing bioprosthetic heart valve (BHV) implantation.

Background:
The medical management of patients undergoing BHV implantation is primarily directed at the management of co-morbid conditions. The anti-atherogenic and anti-inflammatory effects of statin use may contribute to improved clinical outcomes following BHV implantation.

Methods:
A retrospective analysis of patients (n=1957) undergoing aortic (n=1609) and mitral (n=436) BHV replacement with available data on statin use from 2004 to 2013 was performed. All-cause mortality was assessed using the Social Security Death Index. Association of baseline characteristics and statin use during follow-up with the incidence of events was assessed using a time-dependent covariate Cox regression model.

Results:
Follow-up was complete in 100% of patients. Total follow-up time was 3.9 ± 2.4 years during which death occurred in 10% of patients. Pre-discharge statin use was not significantly associated with mortality at 30 days or medium-term follow-up. After adjustment for covariates, post-BHV implantation use of statins was associated with a significant reduction in the risk of all-cause mortality in the entire cohort: HR=0.55, 95% CI: 0.40-0.74, P<0.001. In addition, post-BHV statin use was associated with a decreased risk of all-cause mortality in the aortic valve replacement subgroup: HR=0.59, 95% CI: 0.42-0.84, P=0.003, and mitral valve replacement subgroup: HR=0.30, 95% CI: 0.17-0.54, P<0.001. After exclusion of patients with known CAD (43% of the cohort), post-BHV use of statin therapy remained associated with a lower risk of death: HR=0.51, 95% CI: 0.33-0.80, P=0.004.

Conclusion:
Statin treatment is associated with a significant reduction in medium-term all-cause mortality in patients with and without CAD undergoing aortic and mitral BHV implantation.
Abstract 19575: Prevalence of Abnormal T-wave Inversions in European and American Athletes and its Association with Abnormal Echocardiogram
Authors: Jacob Dany , Magalski Anthony , Gupta Sanjaya , McCoy Marcia
Published: July 2021

Background:
Electrocardiographic (ECG) evaluation is one of the primary tools utilized to screen for increased risk of sudden cardiac death in athletes. Recent study by Sheikh et al. proposed a further refinement to the Seattle criteria, known as the refined criteria. The objective of this study was to compare the prevalence of abnormal T-wave inversions (TWI) using the refined criteria in an American and European cohort and to evaluate the association of abnormal TWI with abnormal echocardiogram in the American cohort.

Methods:
Collegiate athletes at a single university underwent prospective collection of medical history, physical examination, 12-lead ECG, and 2-dimensional echocardiography from 2004 to 2013. ECG analysis of 1755 athletes was performed to asses for TWI as outlined by the refined criteria. Subjects were further classified by race, gender and area of TWI on ECG and compared to 5505 European athletes.

Results:
Of the 1755 American athletes, 49% were males and 1.3% had abnormal TWI. European cohort included 79% males and 3.9% abnormal TWI. Higher prevalence of abnormal TWI were noted in black athletes compared to white athletes in the American cohort (2% and 1.1% respectively). European counterpart had similar findings with 6% of black athletes and 3.3% of white athletes having abnormal TWI. In the American cohort abnormal TWI were distributed unequally within the anterior, lateral and antero-lateral leads (30%, 4% and 65% respectively). Only one American athlete (3.5%) with abnormal TWI had an abnormal echocardiogram.

Conclusion:
Incorporation of ECG assessment has been proposed as part of the preparticipation screening of athletes in United States. Comparison of American and European athletes showed a 67% lower prevalence of abnormal TWI in the American athletes. Only one American athlete with abnormal TWI had an abnormal echocardiogram. We conclude that abnormal TWI alone has a weak association with an abnormal echocardiogram in American college athletes.
Abstract 19588: Angiotensin Converting Enzyme Inhibitors and Mortality Benefit in Systolic Heart Failure Patients With Glomerular Filtration Rate <30 ml/min/1.73 m2
Authors: Inampudi Chakradhari , Cotarlan Vladimir
Published: July 2021

Introduction:
Randomized controlled trials have shown beneficial effect of Angiotensin converting enzyme inhibitors (ACEI) in reducing mortality in patients with systolic heart failure (HF) and chronic kidney disease (CKD) with glomerular filtration rate (GFR) between 30-59 ml/min/1.73m2 but weak evidence exists in patients with GFR < 30

Hypothesis:
We hypothesize that ACEI use is associated with lower mortality in CKD patients with GFR < 30.

Methods:
Using electronic medical records, we identified 2578 patients with advanced CKD defined as GFR < 30 but not on dialysis. We required a GFR < 30 on two occasions over a 60 day period to insure stability of CKD. Clinical outcomes were reviewed following the index date which was the date of first GFR < 30.

Results:
Of 2,578 patients (mean age 66+/-15, 61% males) with advanced CKD (GFR<30), 1,064 (41%) have been treated with an ACEI while 1,514 (59%) never received an ACEI. Kaplan Meyer Survival showed reduced mortality in the group of patients treated with an ACEI compared to those never treated with an ACEI despite more comorbidities present in the former group (mean survival 3.9 vs 4.8 years, p<0.001, Fig 1). Of the patients treated with an ACEI, 232 (22%) continued the ACEI till the end of follow up while 832 (78%) patients discontinued the drug: 93 (9%) prior to index date and 739 (69%) after index date. Survival was significantly better in patients who continued the ACEI than those who discontinued the drug late (after the index date) and those who discontinued early (prior to index date) than in those never treated with an ACEI (Fig 2).

Conclusion:
Treatment with ACEIs is associated with improved survival in CKD patients with GFR < 30ml/min/1.73m2
Abstract 19598: Increased Risk of Repeat Coronary Revascularization is Reduced by Methotrexate or Tumor Necrosis Factor Inhibitor Treatments in Patients With Rheumatoid Arthritis
Authors: Sintek Marc , Sparrow Christopher , Novak Eric , Singh Jasvindar
Published: July 2021

Background:
Rheumatoid arthritis (RA) is a chronic inflammatory condition associated with an increased risk of atherosclerosis and cardiovascular mortality. Long term data on outcomes after percutaneous coronary intervention (PCI) is lacking in this population, specifically with regards to repeat revascularization. We investigated target lesion(TLR) and target vessel revascularization(TVR) in this population.

Methods:
We performed a single center retrospective case control study of RA patients post PCI. Each treated RA lesion was matched to 3 control lesions based upon procedure date, drug eluting stent use, age, vein graft intervention and diabetes mellitus. Patients were censored following the last encounter in the medical record. Primary endpoints were time to TLR and TVR. Kaplan-Meier analyses and shared frailty Cox proportional hazards models were performed to compare event free survival.

Results:
A total of 228 lesions (142 patients) were identified in the RA cohort and matched to 677 control lesions (540 patients). Both groups were followed for a mean of 3.8 years with no difference in repeat catheterizations. There was a trend towards more TLR (HR 1.32; 95% CI 0.97-1.80) and TVR (HR 1.15; 95% CI 0.82-1.62) in RA patients. In the RA group, patients treated with methotrexate or TNF inhibitors showed significantly less TVR (figure 1). This continued to be significant when adjusting for baseline procedural differences (adjusted HR 0.52, 95% CI 0.28-0.98). TLR was also significantly reduced (unadjusted HR 0.46; 95% CI 0.23-0.92) but failed to meet significance after adjustment (adjusted HR 0.69; 95% CI 0.37-1.28).

Conclusions:
RA, a chronic inflammatory condition, may put patients at risk for repeat revascularization after coronary stenting. This risk appears to be reduced by treatment with anti-inflammatory agents. This has implications for the management of RA patients post PCI and may have applicability to other inflammatory diseases such as diabetes.
Abstract 19604: Global Longitudinal Strain in Different Right Ventricular Walls Using Alternate Right Ventricular Apical Views: Validation and Establishment of Normal Values in Children
Authors: Hauck Amanda , Landeck Bruce , Manlhiot Cedric , Dragulescu Andreea , Friedberg Mark , Younoszai Adel , Mertens Luc
Published: July 2021

Introduction:
Right ventricular (RV) function is an important prognostic factor in congenital and acquired heart disease. Quantitative measures of RV lateral wall function obtained from the apical 4 chamber (A4C) view are used to extrapolate global RV function. We aimed to use non-standard views of the RV to establish normal global longitudinal strain (GLS) in additional walls of the RV in healthy children to allow a more comprehensive RV assessment.

Methods:
A total of 88 healthy children (age 5-17 years) were recruited in a prospective, multi-institutional study. Images were acquired with the Vivid E-9 with post-processing performed using EchoPac (GE Ultrasound). RV views similar to LV apical 2 chamber (A2C) and apical 3 chamber (A3C) views were performed with care taken to exclude septal myocardium. GLS in the RV lateral (A4C), inferior (A2C) and posterior (A3C) walls were averaged over 3 cardiac cycles and calculated if at least 2 of 3 wall segments tracked. A global RV strain assessment was calculated by averaging the 3 available walls. Intraobserver variability was assessed.

Results:
GLS was measurable in 67% of lateral, 75% of inferior and 45% of posterior walls analyzed. The normal ranges for GLS across the pediatric age group are shown in figure 1. Overall, we observed a decrease in lateral wall GLS with increasing age; inferior and posterior GLS changed less with age. Average global RV strain was -31.3% +/- 2.4%. Intraobserver reliability in 15 patients showed coefficient of variance of 5.2%, 3.9% and 4% with no significant bias in the lateral, inferior and posterior walls.

Conclusions:
This report establishes reference values for inferior and posterior RV wall strain in children. We show that speckle tracking strain analysis is feasible in alternate walls of the RV allowing for more global assessment of RV function. Establishment of normal values in a larger cohort including younger children may improve future assessment of dysfunction in RV pathology.
Abstract 19616: Ischemic Stress Reduces Cardiac Progenitor Cell Self-renewal Through Gsk3β Activation and Reduction in Cmyc Stability
Authors: Florea Victoria , Barrios Paola A , Lamondin Courtney , Medina Audrey S , Rodrigues Claudia O
Published: July 2021

Introduction:
The adult heart harbors a population of resident stem cells capable of self-renewal and differentiation into cardiac, smooth muscle and endothelial lineages. Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, despite their potential use in cardiac repair, evidence suggests that resident CPCs regenerative capacity is limited in conditions of severe hypoxia such as ischemic cardiomyopathy. Elucidation of the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential.

Methods and Results:
We investigated the growth pattern of murine CPCs under normoxia (21% oxygen) and hypoxia (0.5% oxygen) conditions along a period of 96 hours. We found that CPC proliferation in hypoxia was significantly reduced by 40% after 72-96 hours (p<0.05, n=4-7), without evidence of increase in cell death. CPC proliferation was accompanied with a time-dependent increase in senescence-associated β-galactosidase activity by 30% in hypoxia relative to normoxia control (p<0.02, n=7). Western blot analysis of CPCs grown under normoxia and hypoxia revealed a time-dependent decrease in the expression of the transcription factor cMyc and its downstream target Bmi-1 by 40% and 30% (p<0.05, n=4-5) relative to normoxia control, respectively. Interestingly, reduction in cMyc protein expression was not associated with a decrease in cMyc transcripts, suggesting that cMyc protein degradation is activated under hypoxia. Treatment of CPCs with cycloheximide to block protein synthesis showed that the rate of cMyc degradation under hypoxia is increased by 30% (p<0.05, n=5) relative to normoxia. GSK3β plays a central role in the control of cMyc stability. Growth of CPCs in the presence of GSK3β inhibitor rescued proliferation in hypoxia by approximately 40% (n=4).

Conclusions:
Our results suggest that hypoxic stress reduces CPC self-renewal potential by inducing CPC senescence through a mechanism that involves decrease of cMyc stability through GSK3β activation. Modulation of GSK3β activity may be used as a therapeutic approach for protection of endogenous CPCs self-renewal potential under ischemic conditions.
Abstract 19641: Novel Microprinted Elisa Platform for High Throughput Screening of Protein Secretion Reveals a Comprehensive Strategy to Prevent Ischemia Reperfusion Induced Apoptosis
Authors: Kz Kshitiz , Ellison David E , Afzal Junaid , Hubbi Maimon E , Bernard Segun , Goyal Ruchi , Chang Connie , Abraham Roselle , Levchenko Andre C
Published: July 2021

Introduction:
A major challenge in using stem cells to treat myocardial infarction (MI) is the massive cell death post transplant. Many progenitor cell types limit disrepair post MI without significant cardiac differentiation, possibly by anti-apoptotic signals in their secretions. The signature of these secretions is however not well known.

Methods:
We created a novel high throughput microELISA platform by combining microprinting and microfluidics to precisely estimate secretions of a small population of cells over time. Screening the secretions in many stem cell types used previously to treat MI, i.e. BMSCs (Bone marrow derived stem cells), CDCs (Cardiosphere derived cells), and iPSC-CMs (induced pluripotent stem cell derived cardiomyocytes), we found a common preserved secretory signature of growth factors.

Results:
Using a high throughput screen of pro-apoptotic factors that prevent CDCs from peroxide induced cell death, we surprisingly found that these factors were identical to the preserved secretory signature. Using the constituents of the anti-apoptotic secretory signature in combination with ischemic and mechanical preconditioning in myocardium mimicking rigidity, we created a comprehensive cytoprotective cocktail to prevent CDCs from ischemia induced cell death. We tested the cocktail in a rat model of ischemia reperfusion, and found a stark reduction in CDC retention post injection.

Figures:
(A) MicroELISA schematic. Secretions from cells in left are detected by rows of microprinted capture antibodies; photograph in (C-D). Bioluminescence imaging of CDCs treated with comprehensive cocktail show significantly high cell retention vs untreated CDCs.
Abstract 19656: What is the Prevalence of Familial Hypercholesterolemia in the US?
Authors: de Ferranti Sarah D , Rodday Angie M , Mendelson Michael , Wong John B , Leslie Laurel K , Sheldrick R. C
Published: July 2021

Background:
The prevalence of Familial Hypercholesterolemia (FH) ranges from 1 in 500, as commonly cited, to 1 in 200 in a population-based Danish study. The prevalence of FH in the US, particularly in those of non-European background, remains unknown.

Methods:
To estimate the US prevalence of FH in National Health and Nutrition Examination Survey (NHANES) 2001-2012 datasets (n = 59,423), we used the Dutch Lipid Clinic (DLC) criteria (Benn et al 2012), which classifies individuals as definite or probable FH based on personal history of premature coronary artery disease (CAD), family history in a first-degree relative of known premature CAD or vascular disease, LDL level, and genetic criteria. Genetic testing is not available in NHANES and therefore was not included. For persons reporting statin use, we multiplied by 1.43 to estimate untreated LDL levels.

Results:
The overall US prevalence of probable/definite FH in NHANES was 0.33% (95% CI 0.19-0.48) or 1 in 299 (1 in 210-519). The prevalence of FH was similar in males and females (0.34%; 1 in 293 vs. 0.33%; 1 in 305) and in blacks and whites (0.35%; 1 in 283 vs. 0.37%; 1 in 270), but lower in Mexican Americans (0.16%; 1 in 620) and other races (0.08%, 1 in 1235) and higher in other Hispanics (0.40%; 1 in 252). FH prevalence was lowest in 30-39 year olds (0.15%,
Figure
), and highest in 50-59 year olds (0.60%), and higher with obesity (0.49%; 1 in 204) than non-obesity (0.26%; 1 in 387), likely reflecting the impact of increasing age and weight on LDL when using DLC criteria.

Summary:
Our analysis of NHANES data suggests a US prevalence of FH of 1 in 299, which is higher than the commonly cited estimate of 1 in 500 and is likely an underestimate due to the absence of genetic testing in NHANES. Higher prevalence with obesity and in middle-age highlights the influence of increasing age- and weight-related effects on LDL in FH prevalence estimates. Consideration should be given to incorporating genetic testing into future studies of US FH prevalence.
Abstract 19676: A Molecular Switch Regulating Heart and Pancreatic Development
Authors: Luo Weijia , Weng Kuo-chan , Yu Wei , Dike Donna , Liu Yu , Benham Ashley , Kim Jong , Soibam Benjamin , Xu Xueping , Cooney Austin , Schwartz Robert , Chen Li
Published: July 2021

The mesendoderm is thought to be a population of the intermediate and transient common progenitors
prior to
the emergence of the
me
soderm (Me) and the
en
doderm (En)
in vitro
; however, it is unclear whether it exists
in vivo
, and if so, what are the molecular mechanisms that establish the subsequent Me or En fate of the mesendoderm. Here we show that Mesp1 transiently marks a subset of the epiblast at the
p
rimitive
s
treak (PS) initiation site at gastrulation
in vivo
. It is also evidenced by the cell fate mapping that the progeny of Mesp1
+
progenitors gives rise to both the Me and the definitive En, but neither the primitive En nor the ectoderm, suggesting that Mesp1
+
cells are the bio-potent mesendodermal progenitors.
Mesp1
-fated dorsal foregut En (derived from the definitive En) subsequently contributes exclusively to the Pdx1
+
/Foxa2
+
progenitors in the
p
ancreatic
b
ud (PB), and ultimately to the endocrine cells in the pancreas. RNA-seq and
ch
romatin-
i
mmuno
p
recipitation of
Mesp1
-fated cells show that Mesp1 directly binds to the endogenous regulatory elements of mesendodermal and endodermal modulators (e.g.
Foxa2
). Conditional ablation of
Foxa2
in the
Mesp1
-fated cells results in aberrant PB formation and postnatal death.
In situ
hybridization shows that ablation of
Mesp1
abolishes the majority of mesendodermal modulators while it leads to ectopic expression of endodermal transcription factors in the distal portion of the PS, indicating that transient Mesp1 expression maintains bi-potency of the mesendoderm by inhibiting the endodermal transcription program. We generated chimera embryos by injecting into WT blastocysts the

Mesp1
Cre/+

; Rosa26-EYFP (control) or the

Mesp1
Cre/Cre

; Rosa26-EYFP (mutant) ES cell lines (n=3/group). We found that, the mutant ESCs fail to contribute to the cardiac mesoderm, but instead they adopt the endodermal fate evidenced by their increased contribution to the pancreatic endocrine cells, indicating that the inhibition of the endodermal transcription program by Mesp1 in the mesendoderm progenitors is a cell-autonomous effect. Our results demonstrate that Mesp1 marks the bi-potent mesendoderm
in vivo
and functions as a critical molecular switch between the Me and the En formation
via
an orchestrating dual molecular mechanism.
Abstract 19687: Morphological and Clinical Characteristics of Late and Young Age Onset Apical Hypertrophic Cardiomyopathy: Insight from a 13-Year Registry of Hypertrophic Cardomyopathy
Authors: Chung Hyemoon , Hong Geu-Ru , Son Jungwoo , Cho In-Jeong , Shim Chi Young , Chang Hyuk-Jae , Ha Jong-Won , Chung Namsik
Published: July 2021

Background:
Apical hypertrophic cardiomyopathy (ApHCM) might have different morphological and clinical features according to the age of disease onset, probably result from the distinct mechanism of pathogenesis. The aim of this study was to evaluated the morphological and clinical differences according to the age of disease onset in patients with ApHCM.

Methods:
This was a retrospective, observational study of 56 ApHCM patients (31 males, mean 65±9 years). Among 426 patients with diagnosed ApHCM from 2000 until 2013, we selected 56 patients who met the inclusion criteria: [[Unable to Display Character: ⑴]] patiens who diagnosed with ApHCM before 60 years old and current age >60 years old, (group A, early onset, n=16); and [[Unable to Display Character: ⑵]] who diagnosed with ApHCM after 60 years old who had no evidence of apical hypertrophy confirmed by previous echocardiography (group B, late onset, n=40). Morphological LV feature was assessed by transthoracic echocardiography, which were divided into pure and mixed type. Furthermore, hemodynamic parameters and clinical events were also evaluated.

Results:
There were no differences in the presence of hypertension, LV systolic function and left atrial volume index between group A and B. However, early onset group A had more increased maximal wall thickness of LV apex (17.08±2.02 vs 15.43±1.68mm, p=0.005), and more incidence of pure type (100% (16/16) vs 56.8% (21/40), p=0.001) compare than late onset group B. Group B had older age (65±5 vs 72±4 years, p=0.001), increased LV end-diastolic dimension (51.25±2.32 vs 48.58±3.37mm, p=0.006), increased E/E’ (11.24±2.94 vs 14.60±6.37, p=0.049) with decreased E’ (5.61±1.34 vs 4.66±1.38cm/s, p=0.024) respectively.There were no significant differences in the risk of cardiovascular complication such as atrial fibrillation and stoke between group A and B.

Conclusions:
There was obvious different clinical characteristics according to the age of disease onset. Early onset ApHCM has typical morphological feature and relatively preserved LV diastolic function, compared with late onset ApHCM. Our result supports that late onset ApHCM was related to decreased LV diastolic function and increased LV wall thickness, which reflects the potential myocardial remodeling with aging.
Abstract 19706: CD39/CD73 Pathway in End-stage Human Ischemic Cardiomyopathy
Authors: Novitskaya Tatiana , Su Yan Ru , Maltais Simon , Absi Tarek S , Gumina Richard J
Published: July 2021

Introduction:
CD39 (ectonucleoside triphosphate diphosphohydrolase) is a nucleotidase expressed on endothelial cells, vascular smooth muscles cells, and leukocytes. CD39 plays a key role in vascular homeostasis, hydrolyzing extracellular ATP or ADP to AMP. CD73 (ecto-5’-nculeotidase) hydrolyzes AMP to adenosine. Both CD39 and CD73 are key modulators of purinergic signaling and have been shown to be important in ischemic preconditioning and ischemia reperfusion in animal models.

Hypothesis:
We hypothesized that the expression of the purine nucleotide-metabolizing pathway consisting of CD39 and CD73 in human hearts with ischemic cardiomyopathy is unregulated in response to ischemia.

Methods:
We compared the expression of CD39 and CD73 in left ventricular samples from patients with end-stage ischemic cardiomyopathy and normal hearts. Left ventricular tissue obtained from 7 end-stage ischemic cardiomyopathy hearts and 7 normal hearts not used for transplantation were homogenized and the levels of CD39 and CD73 mRNA were measured by qRT-PCR. Using the same tissue, immunoblot analysis for the protein level of CD39 and CD73 was conducted. Furthermore, immunohistochemical analysis of CD39 and CD73 expression was conducted on left ventricular tissue from the same subjects.

Results:
The total mRNA levels of CD39 and CD73 were increased in patients with end-stage ischemic cardiomyopathy. However, while there was a reduction in the total CD73 protein levels that did not reach significance, there was a marked reduction in the the total protein level of CD39 in ICM hearts (Figure). Immunohistochemical analysis demonstrated that the expression pattern of CD39 was significantly different in ICM hearts compared to normal hearts.

Conclusions:
These data provide important evidence that the extracellular nucleotide metabolizing pathway is altered in ICM. CD39 protein levels are significantly reduced in human end-stage ischemic cardiomyopathy.
Abstract 19811: Circulating Soluble ST2 Levels are Independent of Cardiac Production after Acute Myocardial Injury
Authors: See Vincent Y , Fugate Jessica , Gurm Gagandeep , Ament Dawn , Dickfeld Timm-Michael , Shorofsky Stephen R , Saliaris Anastasios P , Klein Thomas , Remo Benjamin , Christenson Robert , deFilippi Christopher R
Published: July 2021

Background:
Soluble ST2 (sST2) is a decoy receptor that modulates the anti-hypertrophic and anti-fibrotic IL-33/ST2 pathway. sST2 is associated with adverse prognosis in HF and ACS; both states are associated with cardiac injury. However, sST2 levels are also increased in non-cardiac disease. To determine the extent of cardiac production of sST2 both chronically and after acute myocardial injury, we measured fractional cardiac production of sST2 compared to the cardiac specific injury marker high sensitive (hs) cTnT before and after elective cardiac ablation.

Methods:
Twenty-three patients undergoing ablation of atrial fibrillation were enrolled [Caucasian 22 (96%); Male 17 (74%); Age 57.7±10.4 years; eGFR 58.7 ± 0.6 mL/min/1.73m2). Of the 23, 15 (65%) had paroxysmal atrial fibrillation. At baseline, 14 (61%) were in sinus rhythm. Samples were obtained from the radial artery and coronary sinus (CS) pre- and post-ablation. sST2 was measured by the Presage assay. Post ablation samples were measured 201±44 minutes after the first ablation.

Results:
At baseline, in contrast to cTnT, there was no cardiac production of sST2. Both arterial and CS levels of sST2 increased after ablation but not nearly to the extent of cTnT. No net cardiac production of sST2 was noted (Table).

Conclusion:
Cardiac production of sST2 is not observed at baseline. Systemic sST2 levels modestly increase following acute myocardial injury. Despite direct myocardial injury, no cardiac production of sST2 is observed. The source of sST2 is extra-cardiac both chronically and after acute injury.
Abstract 19826: Cardiac DGAT1 Deficiency Decreases Triglyceride Turnover and Alters Substrate Utilization
Authors: Roe Nathan , Tian Rong
Published: July 2021

Triglyceride (TG) metabolism in the heart has been suggested to regulate PPARα activity and fatty acid oxidation. Reduced TG content and turnover has also been shown in rodent models of heart failure. We found that patients with heart failure displayed decreased mRNA levels of diacylglycerol:acyltransferase 1 (DGAT1), the rate limiting enzyme in TG synthesis (0.56±0.06 fold of NF, p=0.0001) and a lower myocardial TG content (3.65±0.41 vs. 8.27±1.48 mg/g tissue in NF, n=8-11, p=0.019). Therefore we hypothesized reduced TG synthesis caused metabolic remodeling in heart failure. In mice with tamoxifen-inducible cardiac specific deletion of DGAT1 (iKO) TG turnover was reduced.
13
C NMR spectroscopy in perfused hearts revealed a 30% reduction in incorporation of labeled fatty acids (FA) into TG in iKO (40 minute peak area 7.86±0.26 vs. 5.73±0.50) with no changes in total TG content. To test whether these changes affect myocardial energetics and contractile function, we simultaneously measured high energy phosphate content and contractile function using
31
P NMR in isolated perfused hearts. Contractile function and PCr/ATP ratio was unchanged in iKO hearts perfused with FA, lactate and glucose. Furthermore, there is no difference between genotypes in the expression of PPARα or its downstream target genes at baseline or after 5 weeks of high fat diet, indicating that TG turnover has minimal effect on PPARα activity. However, iKO hearts showed increased oxidation of exogenous fatty acid (67.0±4.1% vs. 48.5±5.3%) and reduced glucose oxidation (12.9±4.2% vs. 27.4±4.5%, n=5-7). These observations suggest that reduced TG synthesis diverts exogenous FA from the TG pool towards oxidative metabolism. To evaluate the dependence of iKO hearts upon exogenous FA, hearts were perfused with glucose as the only substrate. The ability to utilize TG was reduced in iKO resulting in a 50% higher TG content after 20 min perfusion, which was associated with a reduced left ventricular developed pressure (119±6 vs. 97±7 mmHg for control and iKO respectively). Taken together, we found that DGAT1 deficiency in the heart reduced TG turnover and increased reliance on the oxidation of exogenous FA, a phenotype that may contribute to the lack of metabolic flexibility in heart failure.
Abstract 19831: In Vivo Molecular Imaging of Human Pluripotent Stem Cell-derived Cardiomyocytes in a Murine Myocardial Injury Model via a Safe Harbor Integration of a Reporter Gene
Authors: Rulifson Eric , Matsuura Yuka , Ariyama Miyuki , Wang Mouer , Thakker Rahul , Tachibana Atsushi , Wu Joseph , Yang Phillip
Published: July 2021

Background:
Clinical application of pluripotent stem cells and their tissue specific derivatives will require in vivo monitoring of engraftment and systemic distribution following transplantation. Clinical translation of molecular imaging, employing reporter gene (RG) technology, requires site-specific transgene insertion at safe harbor loci, such as AAVS1.

Hypothesis:
Zinc finger nuclease (ZFN)-mediated integration of a RG into the AAVS1 locus in human embryonic and induced pluripotent stem cells (hESCs and iPSCs) will allow monitoring of pluripotent stem cell-derived cardiomyocytes (hCMs and iCMs) in host myocardium.

Methods and Results:
ZFN technology was used to integrate a triple fusion RG, containing firefly luciferase (BLI), red fluorescent protein (RFP) and herpes simplex virus thymidine kinase (PET), under regulation of a constitutive ubiquitin promoter, into the AAVS1 locus of hESCs and iPSCs. hESCs and iPSCs monoclonal lines were then differentiated into hCMs and iCMs, respectively, under chemically defined conditions using CHIR and IWR small molecules to modulate Wnt pathway activity. Co-localization of cardiac phenotype and striated morphology was readily observed (Fig. A). Site-specific integration was confirmed by southern blot analysis. RG expression by BLI was maintained successfully over 3 months in vitro. The hCMs (n=6) and iCMs (n=1) were transplanted into murine myocardial injury model. Four weeks post-injury, LVEF was better preserved in all cell-treated vs. PBS-treated mice (26.50 ± 2.325 (N=6) vs. 15.40 ± 4.600 (N=3), p<0.05). Robust in vivo expression of ZFN-edited BLI and PET signal of engraftment persisted for 4-weeks duration (Figs. B and C).

Conclusion:
This study demonstrates the successful use of ZFN-edited cells to confirm the engraftment of hCMs and iCMs. ZFN technology enables targeted site-specific insertion of RGs to allow clinical translation of molecular imaging in cell therapy.
Abstract 19839: Clinical and Economic Burden of Rheumatic Heart Disease in Low-Income Nations: Estimating the Cost-of-Illness in India and Uganda
Authors: Sandhu Alexander T , G Kathikeyan , Bolger Ann , Okello Emmy , Kazi Dhruv S
Published: July 2021

Introduction:
Rheumatic heart disease (RHD) strikes young adults at their peak economic productivity. Defining the global economic burden of RHD may motivate investments in research and prevention, yet prior approaches considering only medical costs may have underestimated the cost of illness.

Objectives:
To estimate the clinical and economic burden of RHD in India and Uganda. Outcomes were disability-adjusted life years (DALYs), direct medical costs, and indirect costs due to disability and premature mortality (2012 USD).

Methods:
We used a discrete-state Markov model to simulate the natural history of RHD using country-, age-, and gender-specific estimates from the literature and census data. We estimated direct medical costs from WHO-CHOICE and Disease Control and Prevention 3 publications. We conservatively estimated indirect costs (lost earnings and imputed caregiver costs) from World Bank data using novel economic methods.

Results:
In 2012, RHD generated 6.1 million DALYs in India and cost USD 10.7 billion (Table 1), including 1.8 billion in direct medical costs and 8.9 billion in indirect costs. During the same period, RHD produced 216,000 DALYs in Uganda, and cost USD 414 million, and, as in India, indirect costs represented the majority (88%) of the cost of illness. In both countries, women accounted for the majority (71-80%) of the DALYs; in Uganda, women bore 75% of the total cost. In sensitivity analyses, higher progression rates for subclinical disease doubled direct costs and DALYs.

Conclusion:
RHD exacts an enormous toll on the populations of India and Uganda, and its economic burden may be grossly underestimated if indirect costs are not systematically included. Women bear a disproportionate clinical burden from pregnancy-related complications. These results suggest that effective prevention and screening of RHD may represent a sound public health investment, particularly if targeted at high-risk subgroups such as young women.
Abstract 19842: Microvascular Dysfunction in Patients with ST-Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention: No Sex Disparity
Authors: Chou Annie Y , Wong Graham C , Gao Min S , Park Julie , Taylor Carolyn M , Ramanathan Krishnan
Published: July 2021

Background:
Microvascular dysfunction is highly prevalent in women and presumed secondary to hormonal fluctuations, increased vascular tone, and endothelial dysfunction. Its contribution has never been examined in the acute setting. Patients with ST-elevation myocardial infarction (STEMI) with persistent ST-elevation (ST-E) post successful primary percutaneous coronary intervention (PPCI) are at risk of in-hospital cardiac events. We used ST-E recovery on ECGs pre and post PPCI to study potential sex differences in microvascular dysfunction, in conjunction with cardiac events in a STEMI population.

Methods:
Retrospective analysis was conducted on consecutive STEMI patients undergoing PPCI in Vancouver between May 2007 and September 2010 with evaluable ECGs pre and post PPCI. Patients with bundle branch block were excluded. Quantification of ST-E in each lead was done by electronic calipers by investigators blinded to clinical outcomes. Univariate analysis was performed by sex, for the association between ST-E recovery in the lead with maximal ST-E and the composite of in-hospital mortality, heart failure, cardiogenic shock, and reinfarction.

Results:
Of our 413 patients, 23% were women. In comparing baseline characteristics, age was significantly different (mean age of females = 72 vs. males = 61, p<0.001). More female than male patients had incomplete (<50%) ST-E recovery (20.6% vs. 12.7%, p=0.052). Women with incomplete recovery had an odds ratio of 2.3 for the primary outcome, compared with 1.4 in men, which was not statistically significant between sex. The primary outcome occurred more often in women (29.9% vs. 18.0%, p=0.012), but after adjusting for age, sex difference was no longer significant.

Conclusions:
Female STEMI patients are older, had more incomplete ST-E recovery after PPCI and had more in-hospital cardiac events, although significance was lost after adjusting for age. The higher prevalence of microvascular dysfunction in stable women may not be a large contributor of persistent ST-E in the acute setting. The higher incidence of incomplete ST-elevation in women may be attributable to the increasing prevalence of endothelial dysfunction with age. This novel interaction should be further examined with objective measures.