bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19852: The Relationship Between Obesity and Heart Failure is Stronger than Those for Other CVD Subtypes and Not Explained by Traditional Risk Factors
Authors: Ndumele Chiadi , Matsushita Kunihiro , Lazo Mariano , Bello Natalie A , Blumenthal Roger S , Gerstenblith Gary , Nambi Vijay , Ballantyne Christie , Solomon Scott D , Selvin Elizabeth , Folsom Aaron , Coresh Josef
Published: July 2021

Background:
Although obesity is a risk factor for various subtypes of cardiovascular disease (CVD), the mechanisms responsible for these relationships likely differ. Limited studies have prospectively compared the associations between obesity and CVD subtypes within the same population.

Hypothesis:
We hypothesized that the association of obesity with heart failure (HF) is stronger than those with other subtypes of CVD, and not fully explained by traditional risk factors.

Methods:
We followed 13,730 ARIC participants without CVD at baseline (1987-1989) and with body mass index (BMI) ≥18.5 kg/m2. BMI (kg/m2) was categorized as normal (18.5-24.9), overweight (25-29.9), obese (30-34.9) and severely obese (≥35). Participants were followed prospectively for incident HF, coronary heart disease (CHD), and stroke. Cox regression models with adjustment for demographic and traditional CVD risk factors were constructed to estimate the associations between BMI and CVD subtypes. Seemingly unrelated regression was used to compare coefficients for the different risk associations, to account for correlations in the error terms.

Results:
The mean age was 54 years (SD +/- 6) and 56% were female. Over a median follow-up of 23 years, there were 2,090 HF events, 1,577 CHD events, and 948 strokes. Incident HF demonstrated the highest hazard ratios in association with higher BMI among CVD subtypes in all models, and was the only CVD subtype demonstrating significant associations with higher BMI categories in the fully adjusted model (Table). Indeed, in the fully adjusted model, the risk coefficient between severe obesity and HF was significantly greater than those for CHD and stroke (both p<0.0001).

Conclusions:
The relationship between obesity and HF was stronger than those for other CVD subtypes, and was not explained by traditional risk factors. Research efforts should focus on elucidating non-traditional pathways linking obesity to HF and devising novel preventive strategies.
Abstract 19885: Impact of Cardiovascular Risk Factors on rAAV.Thymosin ß4 Mediated Vascular Regeneration in Large Animals
Authors: Hinkel Rabea , Howe Andrea , Straub Sarah , Husada Wira , Lee Seugmin , Bock-Marquette Ildiko , Renner Simone , Wolf Eckhard , Kupatt Christian
Published: July 2021

Diabetes and hypercholesterolemia are two of the major risk factors for developing cardiovascular disease, especially in combination with chronic myocardial ischemia it represents one of the most common causes of disability or death. New pro-angiogenic factors like Thymosin ß4 (Tß4), a small 4.9 kDa peptide influences cell motility and migration might be suitable for inducing therapeutic neovascularization in chronic myocardial ischemia a cardiovascular risk factors.

Methods:
Chronic ischemia was induced via reduction stent graft in the circumflex artery, leading to a total occlusion on day 28 (d28). Beside wildtyp animals (wt) ± high fat diet (hypercholesteric (hyp), choselsterol 78±1 wt vs 90±2 hyp), d
iabetic transgenic pigs were used (increased blood glucose 305
±12 mg/dL)
.
Regional application of rAAV Tß4 (5x10E12 viral particles, d28) was performed in wt, hyp and diabetic pigs respectively. Global myocardial function was obtained at day 28 and 56. Regional myocardial function and post mortem angiography were examined on day 56. Histological analysis of capillary density (capillaries/field (C/F)) was performed
in the ischemic tissue.

Results:
rAAV.Tß4 transduction significantly enhanced capillaries (278±6 vs. 148±6 c/hpf) and collaterals (9±1 vs. 3±1) compared to control wt animals. Furthermore, global (EF: 47±4 vs. 29±3 %); and regional myocardial function (SES at 150 b/min: 73±5 vs. 10±6 % of non-ischemic area) were increased after Tß4 overexpression. In the models of cardiovascular risk factors and chronic myocardial ischemia increased neovascularization and improved myocardial function could be achieved after rAAV Tß4 application, albeit at a lower level (capillaries: diabetic: 190±4 (Tß4) vs. 120±5 (control) c/hpf hyp: 188±6 (Tß4) vs 130±12 (control) c/hpf; collaterals: diabetic: 4±1 (Tß4) vs. 2±1 (control) hyp: 6±1 (Tß4) vs 3±1 (control); EF: diabetic: 32±2 % (Tß4) vs. 27±1 % (control) hyp: 42±4 % (Tß4) vs 28±3 % (control)).

Conclusion:
Long term Thymosin ß4 expression induced neovascularization and improved myocardial perfusion and function even in pigs with additional risk factors. Therefore, rAAV.Tß4 appears suitable for treatment of ischemic cardiomyopathy associated with these cardiovascular risk factors.
Abstract 19908: 5-oxoprolinase: a Novel Cardiac Mediator of the Oxidative Stress Response in the Failing Heart
Authors: van der Pol Atze , Tromp Jasper , Hoes Martijn F , Domian Ibrahim J , van Gilst Wiek H , Silljé Herman , de Boer Rudolf A , van der Meer Peter V
Published: July 2021

Introduction:
A hallmark of Heart Failure (HF) is the re-emergence of the fetal gene program. The aim of this study was to identify novel genes associated with the fetal gene program in HF, by utilizing a mouse embryonic stem (mES) cell based micro-array.

Methods/Results:
The micro-array analysis was performed on mES cells, early and late mES-derived cardiac progenitors, and mouse neonatal right ventricular tissue. As expected, our screen effectively identified established fetal genes, including alpha smooth muscle actin. We further uncovered several novel genes behaving like fetal genes. The top 5 hits were validated in an in vivo pressure overload HF model. 5-oxoprolinase (OPLAH) was found to be the most significantly differentially expressed gene in the HF model. In a human organ panel, OPLAH gene expression was highest in cardiac tissue, and found to be expressed mainly in the cytosol of cardiomyocytes. Additionally OPLAH protein levels were reduced by 50-70% in both pressure overload and ischemia induced HF (p=0.001 and p=0.009, respectively). OPLAH is an ATP-hydrolyzing enzyme involved in the γ-Glutamyl cycle, responsible for the conversion of the metabolite 5-oxoproline into glutamate. To study OPLAH function we used siRNA and/or over-expression by means of viral transfection of neonatal rat ventricular myocytes. In vitro silencing of OPLAH resulted in an increased susceptibility towards oxidative stress induced apoptosis (40% increase in cleaved caspase-3 positive cells, p=0.02). Furthermore, exogenous administration of 5-oxoproline increased apoptosis in cardiomyocytes (40% increase in cleaved caspase-3 positive cells, p=0.04).

Conclusions:
We identified OPLAH as a novel enzyme associated with HF, behaving like fetal genes, which is involved in the innate protection against oxidative stress, by scavenging excess 5-oxoproline.
Abstract 19931: Echocardiographic Assessment of Volume Status in Hemodialysis Patients: a Study Based on Inferior Vena Cava Diameter and Ventricular Interdependence
Authors: Ren Xiushui , Williams Sherry , Flint Alexander , Feldman Charles , Windust Sharon , Schiller Nelson , Lingamneni Ramesh
Published: July 2021

Background:
It is difficult to assess volume status in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The euvolemic state (dry weight) in ESRD patients is determined clinically but has limitations. We hypothesized that a combination of ventricular interdependence (VI)_the physiologic phenomenon whereby filling of one ventricle is affected by filling of the contralateral ventricle during different phases of the respiratory cycle_and inferior vena cava diameter (IVCd) predicts volume status in ESRD patients undergoing HD.

Methods:
Echocardiograms were performed in 20 patients immediately pre- and post-HD. Clinical assessment of volume status was performed by a single nephrologist blinded to echocardiographic data. VI was defined as peak expiratory to inspiratory mitral inflow E velocity ratio. Hypovolemia was defined as IVCd 20 mm and VI >15%.

Results:
65% of patients were men, and 60% had a history of heart failure. A total of 40 volume clinical assessments were performed (20 pre- and 20 post-HD): 23 were categorized as hypovolemic, 5 euvolemic, and 12 hypervolemic. 21 of 23 (91%) hypovolemic assessments met echo definition for hypovolemia. None of 5 (0%) euvolemic assessments met echo definition of euvolemia. 12 of 12 (100%) hypervolemic assessments met echo definition of hypervolemia. (Figure. Columns and error bars represent mean +/- standard error of mean. P=0.007, Kruskal-Wallis equality-of-populations rank test.)

Conclusions:
In ESRD patients undergoing HD, echocardiographic definition of volume status using IVCd and VI accurately predicts hypo- and hypervolemia. There was poor correlation between echo and clinical volume assessment for euvolemia. This is the first study to examine volume status in HD patients with concomitant cardiac disease using IVCd, and VI. Further studies are needed to determine whether clinical or echo assessment of euvolemia is accurate.
Abstract 20012: Measuring the Sinuses of Valsalva and Left Ventricular Outflow Tract by Cardiac Computed Tomographic Angiography: Incremental Value for Sizing the Valve for Transcatheter Aortic Valve Replacement?
Authors: Rashedi Nina , Durakovic Selma , Gill Edward , Shuman William , Don Creighton
Published: July 2021

Background:
Accurate assessment of aortic annulus size (AoA) is critical for insuring successful transcatheter aortic valve replacement (TAVR) as well as to minimize para-valvular regurgitation. However, the AoA is occasionally difficult to assess due to challenges caused by annular calcification, motion artifact and improper CT gating. Proper TAVR valve size and sealing is dependent more than just AoA, but rather multiple other measurements including the left ventricular outflow tract (LVOT) diameters and sinuses of Valsalva. We hypothesized that the measurement of sinuses of Valsalva and LVOT by cardiac computed tomographic angiography (CCTA) imaging are important adjunctive measurements in determining the ideal valve size for TAVR.

Methods:
Consecutive patients evaluated for TAVR underwent single phase, prospective ECG gated CCTA with contrast to evaluate the aortic valve anatomy. Measurements of annular, coronary height, left ventricular outflow tract diameters and areas were performed. Findings were analyzed using ANOVA and regression models.

Results:
CCTA was performed on 87 patients being evaluated for TAVR. Increasing body surface area (BSA) is weakly associated with AoA and somewhat correlated with sinotubular junction measurements. Sinuses of Valsalva and LVOT are strongly predictive of AoA and the ideal valve size (r
2
=0.66, r
2
=0.86, respectively). Sinuses of Valsalva and LVOT are helpful predictive adjuncts along with AoA in determining the ideal valve size for TAVR, specifically in those with the smallest and largest annular areas (figure 1). Coronary heights were not associated with AoA or BSA.

Conclusion:
There is a strong association between the annulus size and sinuses of Valsalva diameter and LVOT measured by CCTA. This finding is particularly useful in determining the appropriate valve size in those borderline cases or when accurate aortic annulus dimensions are difficult to obtain.
Abstract 20028: Improved Outcomes with IT-enabled Care Management Following Coronary Revascularization
Authors: Elliott Daniel J , Kolm Paul , Weintraub William , Anderson Sharon , Resnik Patty , Steinberg Terry , Lynahan Peggy , Kerzner Roger
Published: July 2021

Objective:
Hospitals are increasingly responsible for the longitudinal care of patients discharged from their institution. We report preliminary results from an IT-enabled care management program for patients following coronary revascularization at a large regional medical center.

Methods:
The program consisted of patient education, telephonic management, and integration with community providers. The intensity of the intervention was tailored to patient risk of subsequent utilization. We used hierarchical logistic regression to compare severity-adjusted all-cause non-elective 30-day readmissions to our institution for all patients discharged in the first year (April 2013 - April 2014) with the baseline period (January 2010 - March 2013). We used mixed effects models to compare patient responses to the Care Transitions Measure-3 (CTM-3), a CMS-endorsed measure of transition quality, and the Seattle Angina Questionnaire-7 (SAQ-7) following discharge, both of which were collected as part of routine care management.

Results:
We enrolled 1,542 revascularized patients in the first year, including 1,188 with PCI and 354 with CABG. The overall rate of readmission for PCI was 7.5% in the baseline period and 8.0% in the intervention period. After adjusting for patient factors, the adjusted rate of readmission was 8.9% and 6.8% (adjusted RR 0.77 [0.76 - 0.78]). The unadjusted rates for CABG were 12.6 and 12.9; with adjusted rates of 13.3 and 10.8 in the baseline and intervention period, respectively (adjusted RR 0.81 [0.8 - 0.83]). The CTM-3 score improved from 67.4±13.3 to 78.8±16.8 for PCI and from 72.7±12.7 to 75±20.7 for CABG during the intervention period (p < 0.001 for both). The SAQ domains all improved significantly during the course of the program, with improvements in Quality of Life Scale from 64±27 to 92±14 for PCI and 60±34 to 92±14 (p<0.001).

Conclusions:
A care management program was associated with improved process and outcome measures, including significant improvements in patient-reported outcomes, when compared to historical controls. Interdisciplinary care management programs can play a significant role in improving care, including in non-integrated healthcare environments.
Abstract 20081: Predicting Risk of Endovascular Device Infection in Patients with Staphylococcus aureus Bacteremia
Authors: Sohail Muhammad , Palraj Bharath Raj , Khalid Sana , Uslan Daniel , Al-Saffar Farah , Friedman Paul , Lohse Christine , Wilson Walter , Steckelberg James , Baddour Larry
Published: July 2021

Objectives:
Clinicians need to identify which patients presenting with
S. aureus
bacteremia (SAB) have underlying cardiovascular implantable electronic device (CIED) infection and therefore need device extraction. The goal of this study was to identify clinical predictors of CIED infection in patients presenting with SAB.

Methods:
We retrospectively reviewed all cases of SAB in CIED recipients at Mayo Clinic from Jan 2001 to Dec 2011. CIED infection was defined using clinical, microbiologic and echocardiographic criteria. Patients who presented with clinical signs of CIED pocket infection were excluded. A multivariable model was developed to identify independent predictors of CIED infection. Model discrimination was summarized using the area under a receiver operating characteristics curve (AUC).

Results:
Among the 131 patients with SAB and CIED, 45 (34%) had underlying CIED infection. Permanent pacemaker (PPM) devices (OR 3.90, 95% CI 1.65-9.23, p=0.002), >1 device-related procedure (OR 3.30, 95% CI 1.23-8.86, p=0.018), and duration of SAB ≥4 days (OR 5.54, 95% CI 3.32-13.23, p <0.001) were independently associated with an increased risk of CIED infection. The AUC for this multivariable model was 0.79 indicating good discriminatory capacity to separate SAB patients with and without CIED infection. Various combinations of these three features and the corresponding predicted probabilities of CIED infection are summarized in
Table.

Conclusions:
An individual patient’s risk of underlying CIED infection can be calculated based on the type of device, number of device-related procedures, and duration of SAB. Patients without any of these high-risk features have very low risk of underlying CIED infection and may be monitored closely without immediate device extraction.
Abstract 20085: Inhibition of Hdac Induces Protective Effects Against Diabetic Cardiomyopathy
Authors: Chen Youfang , Du Jian Feng , Zhao Yu , Zhao Ting C
Published: July 2021

Background:
It is known that inhibition of histone deacetylases (HDACs) protects the heart against ischemic injury. However, it remains unknown whether HDAC inhibition produces the cardioprotective effect in the diabetic heart.

Objective:
We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.

Methods:
Adult ICR male mice received an intraperitoneal injection (i.p.) of streptozotocin (STZ, 200mg/kg) to establish the diabetic model. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate, a specific HDAC inhibitor (1%) in drinking water on a daily basis. Myocardial function was assessed by echocardiography. Cardiac hypertrophy, fibrosis, and myocyte death were evaluated by histological analysis. Western blot was employed to determine the proteins of signaling pathways.

Results:
Left ventricular function was depressed in diabetic mice as compared with control group. HDAC inhibition resulted in an improvement in cardiac function in STZ-injected mice (Table1). Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes. Additionally, sodium butyrate reduced interstitial fibrosis and apoptosis, but increased angiogenesis in diabetic myocardium. Notably, glucose transporter type 1 and 4 (GLUT1, GLUT4) and superoxide dismutase (SOD 1) were elevated following HDAC inhibition in the diabetic myocardium. GLUT1 acetylation was increased in diabetic myocardium following HDAC inhibition.

Conclusion:
HDAC inhibition plays a critical role to reduce cardiac damage in diabetic mice.
Abstract 20086: Influence of Central Apneas and Chemoreflex Activation on Heart Failure Related Pulmonary Arterial Hypertension
Authors: Raglianti Valentina , Giannoni Alberto , Del Franco Annamaria , Mirizzi Gianluca , Aimo Alberto , Iudice Giovanni , Bramanti Francesca , Michele Emdin , Passino Claudio
Published: July 2021

Introduction:
Pulmonary arterial hypertension (PAH) is an acknowledged independent prognostic factor in patients with heart failure (HF). Beyond a “passive” component due to the increased left ventricular pressure, an “active” component due to pulmonary vascular reactivity is frequently observed. However, the mechanism behind pulmonary vasoconstriction is not fully understood.

Hypothesis:
We hypothesized that central apneas (Cheyne-Stokes respiration [[Unable to Display Character: –]] CSR) through chemoreflex stimulation may contribute to PAH in HF.

Methods:
we studied 56 HF patients (left ventricular ejection fraction <50%), on stable optimal pharmacological treatment, without increased left ventriculare pressure (excluding patients with severe mitral disease and severe diastolic dysfunction). All patients underwent echocardiographic and neurohormonal assessment, 24-hour cardiorespiratory screening for CSR (patients with obstructive events were excluded) and chemoreflex test for hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses (by rebreathing technique) .

Results:
Thirteen patients (23%) showed CSR, as defined by a 24 hour AHI > of 15. HF patients with CSR compared with patients with normal breathing, presented higher systolic arterial pulmonary pressure (SPAP: 40.1±7.6 vs 33.1±5.9, p<0.01) at echocardiography, despite similar systolic and diastolic function (data not shown). Furthermore, patients with central apneas also presented with enhanced HVR (median 0.78, interquartile range -IR 0.48-1.22 vs 0.43, IR 0.19-0.69 L/min/%, p<0.05) and HCVR (1.18, IR 0.98-1.35 vs 0.75, IR 0.51-0.95 L/min/mmHg, p<0.01) as well as increased plasma norepinephrine levels (546, IR 371-732 vs 393, IR 229-538 pg/mL, p<0.05). SPAP was indeed correlated with AHI (Spearman’s Rho, R=0.44, p<0.01), HCVR (R=0.48, p<0.001), HVR (R=0.33, p<0.05) and norepinephrine levels (R=0.31, p<0.05).

Conclusions:
In patients with systolic HF, the presence of diurnal-nocturnal CSR, likely via recurrent hypoxia and hypercapnia cycles, may determine a chemoreflex mediated adrenergic discharge and a consequent pulmonary vasoconstriction, responsible of the undesirable increase in pulmonary arterial pressure.
Abstract 20152: Multimerin2 Influences Vascularization Through Modulation of the Extracellular Matrix
Authors: Burgisser Petra E , Tempel Dennie , Cheng Caroline , Pasterkamp Gerard , Duckers Henricus
Published: July 2021

Background:
Vascular development is crucial in normal physiology and pathophysiology, and is in part orchestrated by a dynamic balance between extracellular matrix (ECM) and endothelial cells. The molecular mechanisms that govern this balance and as such play a role in the formation of new blood vessels remain largely unknown.

In order to identify new genes involved in blood vessel formation, we performed a genome-wide gene expression array analysis in Flk1+ angioblasts during mouse development using a commercial platform (Affymetrix). Multimerin2 (Mmrn2) expression was found to be upregulated in angioblasts and endothelial cells and in the developing vasculature of zebrafish and mice.

Methods & Results:
Subsequent
in vitro
studies using an adenoviral construct to induce Mmrn2 overexpression showed a negative effect on angiogenesis. Mmrn2 overexpression resulted in a reduction of 2D tube formation capacity of human aortic endothelial cells (HAECs), as seen in a decrease in the number of junctions and tubules (P<0.05, N=3). Another observed effect after Mmrn2 overexpression was a G0/G1 cell cycle arrest in HAECs (P<0.001, N=8) and decreased migration of the cells in a Boyden chamber assay (P<0.05, N=10).

Further
in vitro
experiments, using immunofluorescence, showed Mmrn2 was detected outside of HAECs, were it co-localized with the extracellular matrix components perlecan, laminin and fibronectin. Direct interaction with these proteins was confirmed using a combination of co-immunoprecipitation followed by proteomics (LC-MS), and western blot to identify possible binding partners. Interestingly, overexpression of Mmrn2 also resulted in enhanced expression of these extracellular components, suggesting that Mmrn2 changes the phenotype from a more proliferative endothelial cell towards a more productive endothelial cell.

Conclusions:
These findings suggest that Mmrn2 is an abundant and important extracellular matrix protein, secreted by endothelial cells, which influences the expression of other ECM proteins such as fibronectin, laminin and perlecan. We hypothesize that Mmrn2 switches the phenotype of the endothelial cell and subsequently diminishes endothelial cell proliferation, migration and overall tube formation.
Abstract 20155: 15-year Outcomes and Predictors of Success for Percutaneous Mitral Commissurotomy for Rheumatic Mitral Stenosis
Authors: Omar AlFazir , Ariff Amin , Zambahari Robaayah , Mohd Ali Rosli
Published: July 2021

Background:
Rheumatic heart disease remains the most common acquired heart disease in children, especially in developing countries. This study aims to investigate the predictors of immediate procedural success and the immediate and long-term outcomes in patients undergoing percutaneous mitral commissurotomy (PTMC).

Methods:
A total of 1552 patients with rheumatic mitral stenosis and underwent PTMC from 1989 to 2012 were identified. We divided the group according to Wilkins score as low risk (≤5), intermediate risk (6-8) and high-risk (≥9). Procedural success was defined as mitral valve area greater than 1.0cm2 with a mean gradient of less than 10mmHg.

Results:
The median age was 36 years old [IQR 28-45]. The majority of patients was female (78.5%) and did not have any other valve involvements (85.0%). Most of cases were elective (99.5%) although 103 patients were pregnant (6.6%) during PTMC. The mitral valve area increased from 0.8cm2 [IQR 0.7-1.0] pre-procedure to 1.5cm2 [IQR 1.3-1.7] post-procedure, with a reduction in the mean pressure gradient of 15mmHg [IQR 12-20] to 4mmhg [IQR 2-6] post-procedure (all p< 0.05). Using logistic regression analysis, no difference was seen in immediate procedural success between increasing age, previous PTMC, emergency cases, New York Heart Association status, balloon size or increasing risk groups (all p>0.05). During the 15-year follow-up, the majority of patients were still alive.

Conclusions:
PTMC appears to be safe and effective in our population, irrespective of older age, higher NYHA class, higher Wilkins score and previous PTMC with good immediate and long-term outcomes.
Abstract 20172: Identifying Hospital Cardiac Services for Acute Myocardial Infarction Using Individual Patient Claims Data
Authors: Chang Tiffany E , Li Shu-Xia , Ranasinghe Isuru , Krumholz Harlan
Published: July 2021

Background:
Hospital data on cardiac services provided is restricted to a limited number of services collected by the American Hospital Association (AHA) Survey. We developed an alternative method to identify hospital services using individual patient administrative claims data for acute myocardial infarction (AMI) in the Premier Database.

Methods:
We first determined inpatient cardiac services relevant for AMI care from guidelines. Then, we identified these services from patient claims using ICD-9, CPT, Medicare Revenue and provider specialty codes. Additionally, Premier Chargemaster and Physician Specialty Codes were used. A hospital was classified as providing a service if they had >5 AMI patient claims for the service in the Premier database from 2009-2011. To measure the accuracy of the claims based method, we compared the percentage of hospitals that were shown to provide a service identified through the AHA survey for a subset of services identifiable from both sources.

Results:
We identified 32 services relevant for AMI care that could be defined using data with inpatient claims among 476 hospitals in the Premier database (Figure). The availability of these services ranged from 100% (for services such as chest x-ray) to 1% for heart transplant service. When compared to the subset of 12 services also collected in the AHA survey, a high percentage of agreement (≥80%) was noted for 10/16 (63%) services (such as a dedicated ED, general CT, coronary angiography, PCI, ICU, pharmacist and physio/OT services). Moderate agreement was seen for one service (coronary care unit), and 5/16 (31%) services showed low agreement (≤50%) (EP testing, inpatient cardiac surgical services, inpatient cardiac rehabilitation, transplant unit, and social worker).

Conclusion:
It is feasible to use claims data to determine in-hospital AMI services, but the accuracy of the method needs to be investigated further for certain services that have a low degree of agreement in our analysis.
Abstract 20190: Sudden Cardiac Death in the Young is Frequently Associated With Cardiac Disease and Drug Use
Authors: Allan Katherine S , Morrison Laurie J , Tu Jack V , Pinter Arnold , Common Matthew R , Patel Dhanisha , Nguyen Brian , Landry Cameron , Dorian David , Dorian Paul
Published: July 2021

Background:
Out-of-Hospital-Cardiac Arrest (OHCA) in young individuals is a tragic and unexpected event, often occurring in seemingly healthy individuals. We examined the etiologies and medications in a large urban cohort of young sudden death patients in order to ascertain the accuracy of this assumption.

Methods:
A prospective population-based registry of all OHCAs in the Toronto area was used to identify cases from 2009-2012. Eligible cases were defined as OHCA patients aged 2-45 who had “no obvious cause” as defined by Emergency Medical Services (EMS) and hospital records, who died, and had a coroner record available. All cases were subsequently classified as primary cardiac or non-cardiac etiology by 3 reviewers (KA, AP, PD) using all available sources of information, including EMS reports, in-hospital data coroner investigative statements, autopsy, toxicology and police reports. Disagreement was resolved by consensus. Cardiac etiology was classified as one of: structural heart disease (HD), ischemic HD, primary arrhythmic, other or undetermined. A positive drug screen was defined as any psychoactive drug, ethanol, or drug of abuse detected at therapeutic, significant or toxic concentrations post-mortem. Cases were further subdivided by age (2-34 vs. 35-45) and gender.

Results:
A total of 470 patients were identified as having adjudicated primary cardiac etiologies. Causes of death and drug information are detailed in Table 1. Both men and women had a relatively high rate of psychoactive drug use (antipsychotics, antidepressants, and opioids). Overall, women had higher rates of medications compared to men.

Conclusions:
Younger, seemingly healthy OHCA patients die more often from structural heart disease than from primary arrhythmia disorders. The high rates of psychoactive drug use, as well as high rates of positive toxicology screens in this cohort suggests that prior illness and drugs may play an important role in the cause of sudden death.
Abstract 20201: Fibro-Adipocyte Progenitors are a Cell Source of Adipocytes in Arrhythmogenic Cardiomyopathy
Authors: Lombardi Raffaella , Chen Suet N , Ruggiero Alessandra , Czernuszewicz Grazyna Z , Gurha Priyatansh , Chen Xiaofan , Willerson James T , Marian Ali J
Published: July 2021

Arrhythmogenic cardiomyopathy (AC) is clinically characterized by arrhythmias, heart failure and sudden death and pathologically by replacement of cardiomyocytes by fibro-adipocytes. Mutations in desmosome genes are the main causes of AC. Desmosome proteins are known to be expressed only in cardiac myocytes. Cardiac progenitor cells (CPCs) expressing mutant desmosome proteins could differentiate to adipocytes. However, genetic fate-mapping identify CPCs as the source of a fraction of adipocytes in AC. We posit that cardiac cells other than CPCs express desmosome proteins and differentiate to adipocytes in AC. We systematically determined expression of the desmosome proteins in different cardiac cells. Cardiac fibro-adipocyte progenitors (FAPs), marked by expression of platelet-derived growth factor receptor-α (PDGFRA), expressed mRNAs and proteins of major desmosome genes. FAPs isolated from the heart of
Nkx2.5Cre:Dsp
W/F
mice, an established model of AC, showed enhanced adipogenesis associated with suppression of canonical Wnt signaling (reduced
Ccnd1, Ctgf
and
cMyc
mRNA levels by 10-, 5- and 3-fold, respectively, N=5, all p<0.001). To determine whether FAPs are a source of adipocytes in AC, we generated lineage tracer mice, utilizing the
Pdgfra-Cre
deleter, and conditionally deleted one copy of desmoplakin (
Dsp
) while expressing enhanced yellow fluorescence protein (EYFP) in the FAPs. Recombination efficiency (% of PDGFRA+ cells expressing EYFP) was ~75%. Six to 12 months old lineage tracer mice (

Pdgfra-Cre:Dsp
W/F
)

showed mild cardiac dysfunction (fractional shortening: 57±9%, N=14 vs. 66±7%, N=10 in controls, p< 0.005) and increased adipocytes in the heart (14±9, N=5 vs. 1±1, N=3 in controls, p=0.03). Co-expression of EYFP and C/EBPA adipogenic marker was detected in 54% of adipocytes in the lineage tracer mice, indicating an origin from FAPs.
Dsp
+/-
FAPs showed enhanced differentiation to adipocytes as compared to control FAPs. The Hippo, canonical Wnt and NOTCH1 signaling pathways in mediating differentiation of
Dsp
+/-
FAPs to adipocytes are being delineated. The findings show cardiac FAPs express desmosome proteins and when haplo-insufficient for
Dsp
differentiate to adipocytes. Thus, FAPs are a source of adipocytes in AC.
Abstract 20287: Cardiac MIBG Imaging Predicts Cardiac Death in Patients With Chronic Heart Failure , Irrespective of Hyperuricemia
Authors: Takahashi Satoshi , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Kawai Tsutomu , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Sato Yoshihiro , Seo Masahiro , Fukunami Masatake
Published: July 2021

Background:
Elevated uric acid level is associated with an increased risk of adverse outcome in patients with chronic heart failure (CHF). On the other hand, cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with CHF. However, there is no information available on the prognostic value of cardiac MIBG imaging in CHF patients, relating to hyperuricemia.

Methods:
We enrolled 113 CHF outpatients (NYHA2.0±0.6, ischemic origin 48%) with radionuclide LVEF <40%(30±8%). The cardiac MIBG washout rate (WR) was calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. Abnormal WR was defined as >27% as reported previously. At the entry, we measured serum uric acid level and hyperuricemia was define as >7.0mg/dl. The primary end point was cardiac death.

Reults:
At the entry, 59 and 51 of 113 patients had abnormal WR and hyperuricemia, respectively. Serum uric acid level was significantly higher in patients with than without abnormal WR (7.3±1.8 vs 6.3±2.0 mg/dl, p=0.007). During the follow up period of 7.6±4.3 years, 35 patients had cardiac death. Cardiac death was significantly more often observed in patients with than without abnormal WR (47% vs 13%, p<0.001) and hyperuricemia (42% vs 23%, p=0.034). At multivariate Cox analysis, abnormal WR and hyperuricemia were significantly independently associated with cardiac death (p=0.02 and p=0.03, respectively). Patients with abnormal WR had a significantly greater risk of cardiac death than those with normal WR in group with hyperuricemia (p=0.004, harard ratio: 6.5, 95%CI 1.8 to 23.4) and without hyperuricemia(p=0.001, hazard ratio: 4.4, 95%CI 1.5 to 13.2).

Conclusion:
Cardiac MIBG imaging provides the additional information to hyperuricemia in CHF.
Abstract 203: Supporting the Potential Use of the Thoracic Impedance Signal to Detect Return of Spontaneous Circulation
Authors: Alonso Erik , Aramendi Elisabete , Ayala Unai , González-Otero Digna , Daya Mohamud , Russell James K
Published: July 2021

Background:
During resuscitation, checking for a carotid pulse to recognize cardiac arrest or detect the return of spontaneous circulation (ROSC) has been shown to be both inaccurate and time-consuming. More recently, an abrupt sustained increase in end-tidal carbon dioxide (EtCO2) to a normal value (35 to 40 mmHg) has been accepted as an indicator of ROSC. During ROSC the thoracic impedance (TI) signal shows a circulation component (ICC) with small fluctuations with each heartbeat. Mean amplitude of 40.04 mΩ has been reported for the ICC in pulse-generating rhythms, and 6.03 mΩ in pulseless electrical activity.

Aim:
To analyze the relationship between EtCO2 and ICC amplitude in order to assess the potential use of the TI for circulation detection during resuscitation.

Methods:
A sample of 203 ROSC segments (mean duration 8.9±4.2 s) containing ECG, TI and capnography signals were extracted from 40 cardiac arrest episodes recorded by Tualatin Valley Fire & Rescue (Tigard, Oregon) using the Philips MRx devices. An adaptive scheme based on a least mean square algorithm was used to estimate the ICC from the TI using as reference the instants of the QRS complexes automatically detected in the ECG. The EtCO2 and the mean peak-to-trough amplitude of the ICC were computed per segment and their distributions analyzed. For all the segments, univariate linear regression was used to fit a model to predict the EtCO2 value, C, based on the amplitude of the ICC, A. The linearity was tested with the Pearson correlation coefficient, R.

Results:
Mean values were 54±20 mmHg and 53.1±34.1 mΩ for EtCO2 and ICC amplitude respectively. High levels of EtCO2 were clearly associated with high ICC amplitudes, although the linearity between EtCO2 and ICC amplitude was low (R=-0.22).

Conclusion:
High levels of EtCO2 are linked to high ICC amplitudes, which supports the potential use of TI signal as ROSC indicator in resuscitation scenarios where capnography is not available.
Abstract 20310: Cardiovascular Risk Markers in a Large Cohort of Children With Genetically Verified FH Show No Inheritance-Related but LDL Receptor Mutation-Type and Family History of CVD-related Variance
Authors: Narverud Ingunn , van Lennep Jeaninen R , Christensen Jacob J , Versmissen Jorie , Gran Jon M , Iversen Per O , Ose Leiv , Aukrust Pål , Halvorsen Bente , Ueland Thor , Ulven Stine M , Veierød Marit B , Sijbrands Eric , Retterstøl Kjetil , Holven Kirsten B
Published: July 2021

Introduction:
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused primarily by mutations in the low density lipoprotein (LDL) receptor gene. FH patients have increased total- and LDL cholesterol leading to accelerated atherosclerosis and premature cardiovascular disease (CVD). In an FH pregnancy the absolute rise in lipid levels are often much higher than in healthy pregnancies, and this maternal hypercholesterolemia

may thus contribute to an unfavorable
in utero
environment potentially increasing susceptibility of adult CVD. Few studies have investigated whether maternal FH is associated with an unfavorable phenotype in offspring compared with paternal FH inheritance.

Hypothesis:
The aim of the present study was to investigate the impact of maternal
vs.
paternal FH on pre-treated plasma lipids. In addition, the effect of LDL receptor mutation types and Family history of early CVD in FH children was evaluated

Methods:
We included 1063 children with FH (0-19 years) in the study. Five-hundred had inherited FH maternally and 563 paternally. Furthermore, 624 children with FH had an LDL receptor negative mutation and 332 of the FH children had an FH grandparent suffering from early CVD whereas the remaining children had an FH grandparent with late or no CVD. Differences were tested for using a random intercept mixed model taking account for between-family variation.

Results:
Children with maternal FH did not have different levels of total-, LDL- or HDL-cholesterol, triglycerides, apoA1, apoB, lipoprotein (a) compared with children With paternal FH. Moreover, children with LDL receptor negative mutations had higher levels of total- and LDL cholesterol in addition to apoB, and concomitantly lower levels of HDL-cholesterol and apoA-1 than children with other LDL receptor mutations. Finally, children with an FH grandparent with early CVD had significant higher LDL-cholesterol levels than children without.

Conclusions:
Maternal FH does not lead to a more unfavorable

phenotype in untreated FH children. However, both FH children with LDL receptor negative mutation and FH children with early CVD in family had a more unfavorably phenotype. Hence statin treatment should potentially be initialized earlier in this group.
Abstract 20311: MYBPC3 Mutations Causative for Hypertrophic Cardiomyopathy Result in Locus-Dependent Alterations in Cellular Localization and Contractility
Authors: Helms Adam S , Glazier Amelia , Bartolone Sarah , Tang Vi , Yob Jaime , Westfall Margaret , Schnell Santiago , Day Sharlene M
Published: July 2021

Introduction:
Mutations in MYBPC3 resulting in truncated proteins are the most common genetic cause of hypertrophic cardiomyopathy (HCM). Whether lack of sufficient MYBPC3 protein is the primary disease mechanism is controversial. We hypothesize instead that truncated MYBPC3 proteins exert dominant-negative effects on sarcomere structure and function.

Methods and Results:
MYBPC3 mutations resulting in short (Ile154LeuFs*5, 17 kD) or long (Asp1076Valfs*6 and Trp1098*, each ~120 kD) truncated proteins were studied. For each truncated protein, in silico analysis (I-TASSER) predicted marked deviation from the predicted wild-type (WT) structure. Immunofluorescence of adenoviral-expressed proteins in neonatal rat ventricular cardiomyocytes revealed that WT MYBPC3 was correctly localized at sarcomere A-bands. Near-complete mislocalization (predominantly nuclear) was observed for Ile154LeuFs*5 MYBPC3. Both Asp1076Valfs*6 and Trp1098*MYBPC3 mutant proteins localized imprecisely within the sarcomere, but also were diffusely present in the cytosol. Western blot of myofilament preparations confirmed no sarcomere incorporation of Ile154LeuFs*5, and reduced incorporation of Asp1076Valfs*6 and Trp1098* truncated MYBPC3 (Asp1076Valfs*6 28.1+0.4% and Trp1098* 20.3+0.2% vs. WT 72.4+0.2%, p<0.001). Ile154LeuFs*5 MYBPC3 was exclusively present in the non-myofilament fraction, while Asp1076Valfs*6 and Trp1098* MYBPC3 were 3-fold enriched in this fraction (p=0.01). Analysis of sarcomere shortening (Ionoptix) in adenoviral-infected adult rat ventricular cardiomyocytes indicated reduced peak shortening for Trp1098* (5.30+0.92% vs. WT 8.35+0.49%, p<0.05) and time to peak contraction (43+2 ms vs. WT 67+3 ms, p<0.05). In contrast, no significant effect of Ile154LeuFs*5 MYBPC3 on cellular contractility was observed.

Conclusions:
Truncating MYBPC3 mutations are predicted to markedly alter protein structure. Longer truncated proteins partially incorporate into the sarcomere lattice and alter contractile function while shorter truncated proteins accumulate in other cellular compartments. These results suggest distinct mutation-specific negative effects of truncating MYBPC3 mutations on myocyte function.
Abstract 20343: Leptin and the Developmental Origins of Hypertension
Authors: Pitz Kate M , Peotta Veronica A , Volk Kenneth A , Rahmouni Kamal , Roghair Robert D
Published: July 2021

Introduction:
Individuals with growth restriction through 2 years of age are relatively protected from adult obesity, but they are at increased risk of adult hypertension. Modeling this in mice, neonatal growth restriction (GR) leads to neonatal leptin deficiency, impaired neurodevelopment, adult growth restriction and adult hypertension.

Hypothesis:
We hypothesized that neonatal leptin deficiency during a window of developmental plasticity permanently increases central leptin sensitivity with subsequent renal sympathetic over-activation and hypertension.

Methods:
From day 4 to 14, C57BL/6 mice were randomized to vehicle (0.9% NaCl) or leptin at a dose shown to normalize the plasma levels of GR mice without impacting neonatal growth (1 mg/kg/d, intraperitoneal). GR mice were identified by weanling weights below the 10th percentile. Beginning at 4 months, adult phenotypes were assessed.

Results:
Compared to normal weight controls, adult GR mice had significantly increased leptin receptor mRNA expression within the arcuate nucleus of the hypothalamus (ARC), decreased adult food intake (0.09±0.01 vs. 0.13±0.02g/g/d; p<0.05), decreased adult body weight, and exaggerated leptin-triggered increases in both renal sympathetic nerve activity (29+/-11 vs. -9+/-6% change from baseline, p<0.01 for GR versus control) and systolic blood pressure (8+/-3 vs. -1+/-6% change from baseline, p<0.05 for icv leptin versus icv saline in GR mice). Leptin supplementation normalized the hypothalamic gene expression and leptin responsiveness of GR adult mice in association with a programmed suppression in leptin-triggered activation of signal transducer and activator of transcription 3 (STAT3).

Conclusions:
Neonatal GR-related leptin deficiency is associated with a sustained increase in ARC leptin receptor expression and enhanced adult leptin responsiveness. This heightened central leptin responsiveness may contribute to the increased risk of hypertension seen patients with a history of perinatal growth restriction. We are currently assessing the effects of neonatal GR and neonatal leptin administration on cell-specific leptin-mediated hypothalamic signaling pathways.
Abstract 20350: Discordant Left Bundle Branch Block is Associated With Left Ventricular Dyssyncrhony at Cardiac Magnetic Resonance Imaging in Patients With Nonischemic Cardiomyopathy
Authors: Valleggi Alessandro , Emdin Michele , Aquaro Giovanni D , Passino Claudio , Vergaro Giuseppe , Barison Andrea , Pastormerlo Luigi E , Padeletti Luigi
Published: July 2021

LBBB is frequently linked to left ventricular (LV) dyssynchrony and adverse prognosis in HF. LBBB has been defined as concordant (cLBBB) or discordant (dLBBB), when associated in lead I and V5, V6 with a positive or negative T wave respectively. dLBBB has been associated with a worse clinical and prognostic profile in HF patients. We sought to evaluate association between different patterns of LV dV/dT curves at CMR, LBBB morphology, clinical correlates and prognostic role in patients with nonischemic systolic HF.

Methods and Results:
One hundred and fifteen consecutive patients with LBBB were submitted between 2004 and 2014 to a complete cardiological evaluation, including CMR with analysis of dV/dT curves of LV contraction, and follow-up for cardiac events. We distinguished two different patterns of global and segmental LV systole: a “narrow” pattern (NP) generated by synchronous contraction of wall segments; a “wide” pattern (WP), when delay in contraction between wall segments resulted in a prolungation of systolic peak with a flat or notched morphology. Fourteen patients presenting with normal LV dimensions and function all had cLBBB and NP, while out of 101 patients with HF, those with dLBBB (65%) presented with shorter QRS duration (p < .01) and higher level of NT-proBNP (p < .001). WP was observed more frequent in dLBBB patients (p < .003) as a mark of greater intraventricular dyssynchrony. According to systolic pattern, those with WP had higher levels of NT-proBNP, lower EF and higher LV volumes than those with NP, whereas no significant difference was found in QRS duration. At multivariate analysis only dLBBB (p=.006) and EF (p=.001) were independent predictors of WP. At Kaplan-Meier analysis, the presence of WP was associated with a worse prognosis considering a composite end-point of cardiac death, hospitalization for HF and ICD shock (p<.005). At Cox analysis only presence of WP (p = .029) and level of NT-proBNP (p= .004) were independent predictors.

Conclusions:
In nonischemic systolic HF patients with LBBB, presence of a WP at CMR dV/dT curves is associated with dLBBB, identifies greater LV dyssynchrony with possible major benefits from resynchronization therapy and is an independent prognosticator.