bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18004: Diagnosis of Obstructive Sleep Apnea in Patients With Congenital Long QT Syndrome
Authors: Shamsuzzaman Abu , Szczesniak Rhonda , Fenchel Matthew , Amin Raouf
Published: April 2024

Introduction:
Obstructive sleep apnea (OSA) is a common health problem which affects about a quarter of US adults. OSA is increasingly linked to cardiovascular diseases including hypertension, heart failure, myocardial infarction, cardiac arrhythmias and sudden cardiac death (SCD). Congenital long QT syndrome (LQTS) is a common cause of SCD in children and young adults during exercise and sleep. LQT3 (SCN5A) and LQT2 (HERG) genotypes are particularly at increased risk for SCD during sleep. We tested the hypothesis that increased numbers of patients with congenital LQTS have OSA compared to controls matched for age gender and BMI.

Methods:
A complete medical history and a standard 12-lead surface ECG were obtained in LQTS and controls. Polysomnography (PSG) was conducted in 32 LQTS patients (20 LQT1 and 12 LQT2) and 40 controls matched for age, gender and BMI. Blinded interpretation of the sleep studies were carried out by a single investigator board certified in Sleep Medicine. OSA was defined by the presence of AHI ≥5 events/hour for adults (≥18 years) and >1 event/hour for children (<18 years).

Results:
The PSG results show that 16 LQTS patients (50%) have clinically significant OSA compared to 6 controls (15%) in the controls. There are 7 LQTS patients who have history of early childhood adenotonsillectomy and only 2 of them have OSA on the PSG results. Considering very close relationship between adenotonsillar hypertrophy in children and OSA, these children might have OSA in early childhood. Therefore, total 21 LQTS patients (65%) have OSA on the PSG and/or adenotonsillectomy. Presence of OSA is equally distributed in LQT1 and LQT2 genotypes.

Conclusion:
OSA is more common in patients with congenital LQTS compared to healthy matched controls. Apneic events during sleep are associated with exaggerated sympathetic responses which might be potential mechanisms for triggering arrhythmias and thus increased risk of SCD during sleep.
Abstract 18011: The Impact of Institutional Stage I Surgical Volume on Mortality, Length of Stay, and Hospital Charges in Infants With Hypoplastic Left Heart Syndrome, a Review of the Texas Inpatient Public Use Data File From 1999-2012
Authors: Tunuguntla Hari P , Nembhard Wendy , Ethen Mary K , Canfield Mark A , Fixler David E , Morris Shaine A
Published: April 2024

OBJECTIVE:
Studies to date have suggested an association between center surgical volume and lower mortality in children undergoing heart surgery. While this has been investigated in national sampled data and registries, contemporary statewide data specifically relevant to public health insurance have not been investigated in detail.

METHODS:
The Texas Inpatient Public Use Data File, a database of hospital discharges in the state of Texas, was queried from 1999-2012. Infants with the diagnosis of HLHS undergoing a Stage I Palliation (S1P) as defined by an aortopulmonary shunt (ICD-9 39.0) or right ventricle to pulmonary artery conduit (35.92) were included. Univariable and multivariable analyses were used to investigate the relationship between center S1P surgical volume and hospital mortality, length of stay, and total charges. The association between insurance status and race/ethnicity and mortality were also investigated.

RESULTS:
Of >37 million discharges, 780 infants with HLHS underwent S1P at 14 hospitals. The mean number of annual S1Ps at each hospital varied from <1 to 16.1 with 53% of infants undergoing surgery at a center with >15 S1Ps/year. Fifty-four percent of the infants were covered by public insurance. In univariable analysis, lower surgical volume was associated with increased mortality, with mortality in hospitals performing <5 surgeries per year 30.6%, 5-15 surgeries per year 27.1%, and >15 surgeries per year 15.6% (p for trend<0.001). Higher surgical volume was not associated with length of stay (Rho=0.004) or total charges (Rho=0.057). In multivariable analysis, adjusting for discharge year and preterm birth, lower surgical volume remained associated with increased mortality (compared to >15 surgeries/year, <5/year 2.62, 95%CI 1.78-3.85, 5-15/year 2.44, 95%CI 1.40-4.28). No categories of race/ethnicity or insurance status were associated with increased mortality.

CONCLUSION:
Institutions with higher Stage I surgical volume had lower HLHS hospital mortality, without increased charges or length of stay. Given the large population of infants covered by public insurance, governmental health care plan support of regionalization of care in neonatal HLHS has the potential to improve mortality rates in this population.
Abstract 18013: Which Measure of Renal Function is the Best Predictor of Outcome in Heart Failure? A Comparison of Cockcroft Gault, Modification of Diet in Renal Disease Study Group and Chronic Kidney Disease Epidemiology Collaboration Formulae
Authors: Pozzi Andrea , Jhund Pardeep , Perez-Moreno Ana Cristina , van Veldhuisen Dirk J. , Böhm Michael , Wikstrand John , Cleland John , Kjekshus John , Petrie Mark , McMurray John
Published: April 2024

Introduction:
Renal function is an important predictor of prognosis in heart failure (HF). Several formulae can be used to estimate glomerular filtration (eGFR) but which of these is best at predicting outcome in HF is uncertain. We compared the performance of the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study Group (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in predicting all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF).

Methods:
We studied the 5011 patients aged ≥60 years with symptomatic (NYHA class II-IV) HF of ischemic etiology and a LVEF ≤40% (≤35% in NYHA class II) enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure trial (CORONA). Mortality rates were calculated for patients in the eGFR categories <45, 45-59 and ≥60 ml/min/1.73m
2
(reference). The performance of the equations was compared using receiver operating characteristic curve (ROC) analysis.

Results:
The rate and risk of death was highest in those with the lowest eGFR for each formula (Table). The area under the ROC for CG was 0.64, MDRD 0.59 (P<0.001 versus CG) and CKD-EPI 0.61 (P<0.0001 versus CG).

Conclusion:
Risk prediction with CG was better than with MDRD or CKD-EPI in patients with HfrEF in CORONA.

†Rate per 100 patient years *Reference group
Abstract 18024: The Efficacy and Safety of Rivaroxaban vs Warfarin in Patients Undergoing Atrial Fibrillation Ablation: A Meta-Analysis
Authors: Gangireddy Sandeep R , Koh Anna P , Bockstall Katy E , Keane Stephen , Fisher Alexander M , Koruth Jacob , Miller Marc A , Dukkipati Srinivas , Reddy Vivek Y
Published: April 2024

Introduction:
Rivaroxaban, an oral direct factor Xa inhibitor, is an alternative to warfarin for stroke prophylaxis in patients with atrial fibrillation (AF). Patients are increasingly undergoing AF ablation while taking rivaroxaban, but little is known regarding the safety of this approach.

Methods:
We performed a meta-analysis of studies which compared the use of peri-procedural rivaroxaban with warfarin in patients undergoing AF ablation. We identified 1 published randomized controlled trial and 5 abstracts; 3 observational studies with control groups, and 2 observational studies without control groups. Embolic complications were defined as stroke/TIA or pulmonary embolism, and bleeding complications as all major events requiring transfusion and minor events including pericardial effusion, femoral hematoma, and GI bleeding. Studies were stratified according to controlled vs. uncontrolled study design, and analyzed using the Mantel-Haenszel fixed effect model.

Results:
There were a total of 634 patients on rivaroxaban, and 479 patients on warfarin undergoing AF ablation. Mean age was 63, and CHADS2 score ranged from 0.9-3. Rivaroxaban was held 12-48 hours pre-procedure, resumed 6-24 hours post-procedure, and in 224 (35%) was uninterrupted. The composite embolic rate was 1.7% in the rivaroxaban group, and 1.5% in the warfarin group (p=NS). The composite bleeding rate was 11.5% the rivaroxaban group, and 10.5% in the warfarin group (p=NS). Meta-analysis using controlled studies (410 rivaroxaban vs. 479 warfarin patients) showed no difference in embolic complications (OR, 0.791; 95% CI, 0.246-2.541) and bleeding complications (OR, 1.214; 95% CI, 0.790-1.867) between the two groups (Figure).

Conclusion:
Rivaroxaban may be a safe alternative to warfarin anticoagulation in patients undergoing AF ablation. Further randomized controlled trials are needed to determine its relative safety and efficacy compared to warfarin peri-ablation.
Abstract 18033: The Contribution of Cardiovascular Spending to Total Inpatient Spending for High-Cost Patients
Authors: Joynt Karen E , Gawande Atul , Orav E. John , Jha Ashish
Published: April 2024

Spending in the Medicare program is concentrated among a small group of patients. As novel payment mechanisms such as bundled payments and accountable care organizations proliferate, there is increasing importance to understanding where these patients’ costs originate. Cardiovascular care is an area of focus, due to the high costs and expensive technologies used within the field. However, the contribution of cardiovascular spending to total inpatient spending for high-cost patients is unknown. We used standard 5% Medicare inpatient and outpatient files from 2009 and 2010 to evaluate the proportion of inpatient spending related to cardiovascular disease for high-cost patients (top 10% of spenders in 2010) and persistently high-cost patients (top 10% of spenders in 2009 and 2010). We classified all admissions using ICD-9 codes into clinical categories. We found that costs for cardiovascular care were highly concentrated, with 77% of cardiovascular inpatient spending from the 10% of patients in the high-cost cohort, and 25% of spending from the 3% of patients in the persistently high-cost cohort. Furthermore, cardiovascular care made up a significant proportion of total hospital spending for the high-cost cohort. Ischemic heart disease, congestive heart failure, arrhythmias, stroke and transient ischemic attack, peripheral atherosclerosis, cardiac valvular disease, and angina made up 22.6% of inpatient spending for high-cost patients and 19.7% of inpatient spending for persistently high-cost patients (Table). Projected to the national Medicare population, these admissions cost more than $10 billion in 2010. In conclusion, cardiovascular spending is highly concentrated, and cardiovascular disease comprises a large portion of inpatient spending for the most expensive Medicare patients. There is a tremendous opportunity for the cardiovascular community to target high-cost patients and pursue care redesign to lower costs for these common conditions.
Abstract 18040: Evidence for Increased mTORC1 and mTORC2 Signaling in Human Thoracic Aortic Aneurysm
Authors: Jbeli Aiham H , Hagler Michael A , Kunkala Meghana , Roos Carolyn M , Sundt Thoralf M , Miller Jordan D
Published: April 2024

Thoracic aortic aneurysm (TAA) is a prominent condition that can progress to both aortic dissection and rupture, and has a higher prevalence in patients with bicuspid aortic valves. While smooth muscle cell proliferation and matrix remodeling are hallmarks of TAA, mechanisms regulating these phenomena are poorly understood. Thus, we tested the hypothesis that mTOR signaling, a positive regulator of cell proliferation and matrix remodeling enzyme elaboration, is increased in human TAA samples from patients with tricuspid and bicuspid aortic valves. Tissue was acquired at the time of operation, and mTOR activation was measured in aortic tissue from patients with TAA and tricuspid aortic valves (n = 29), TAA and bicuspid aortic valves (n = 29) and normal, non-aneurysmal aortic tissue from organ donors (n = 13). qRT-PCR expression of mTOR (1.29±0.1), Raptor (1.31±0.09, an mTORC1-specific subunit), and Rictor (1.44±0.1, an mTORC2-specific subunit) was significantly increased in tricuspid TAA samples compared to normal aorta (1 ±0.1; p < 0.05 for all). Similar changes were observed in patients with bicuspid TAA, as expression of mTOR (1.33±0.04), Raptor (1.27±0.06) and Rictor (1.65±0.09) were increased compared to normal (p < 0.05 for all). Importantly, protein levels of p-S6K and p-4E-BP1, both of which are well-defined targets of mTORC1 signaling, were increased by approximately two-fold in bicuspid and tricuspid TAA samples compared to normal aorta. Collectively, to our knowledge, this is the first report suggesting increased activity of both mTORC1 and mTORC2 signaling in human thoracic aortic aneurysm. We propose that inhibition of mTOR signaling may be a useful and efficacious intervention to inhibit cellular proliferation and matrix metalloproteinase activation in TAA, ultimately slowing aneurysmal dilatation and progression to aortic dissection and rupture.
Abstract 18056: High Dose Beta Blocker Use Does Not Increase the Frequency of Allergic Contrast Reaction in Coronary CT Angiogram Examinations: Results From the Advanced Cardiovascular Imaging Consortium
Authors: Aggarwal Anshul , Smith James , Mehta Neesurg , Boura Judith , Raff Gilbert , Lauter Carl , Chinnaiyan Kavitha
Published: April 2024

Background:
A higher incidence of contrast reactions have been reported in atopic patients with the use of high dose beta blockers. High dose beta blockers are often used for heart rate control during coronary CT angiography (CTA) examinations. We sought to identify allergic complications in a large, multicenter, CTA registry.

Methods:
Patients undergoing coronary CTA at 53 Michigan institutions from January 2009 to March 2013 and participating in the ACIC were retrospectively analyzed. Patients were separated into two categories, those with and those without history of contrast allergy. Exposure to beta blockers was noted, and allergic reactions during or after CTA examinations were noted. Allergic reactions were defined as rash/hives, respiratory complications, anaphylaxis, generalized itching, wheezing, and face swelling immediately after completion of CT coronary angiogram.

Results:
Overall, 60 out of 26,725 patients included in the analysis had allergic complications (0.2%). Of the patients without a history of atopy that received high dose beta blocker, 42 out of 20206 (0.2%) patients had allergic complications when compared to 9/4725 (0.2%) of patients without high dose beta blockers (p= 0.81).

Of the patients with a history of allergy in the past, 8/876 (0.9%) had allergic complications as compared with 52 out of 24,931 (0.2%) of patients without a history of allergy (p=0.002). Among allergic patients who received beta blockers, there were 7 out of 779 patients (0.9%) that had allergic complications when compared to 1 out of 97 patients (1.0%) who did not receive beta blockers (p=1.00).

Conclusions:
The overall incidence of allergic complications in patients undergoing coronary CT angiography is very low. The incidence of allergic reactions is higher in patients with a prior history of contrast allergy. There was no impact of high dose beta blockers on the incidence of contrast allergy in atopic patients.
Abstract 18065: The Upregulation of MicroRNA miR-21 Mediates Concentric Left Ventricle Remodeling in a Rat Model of Chronic Renocardiac Syndrome
Authors: Kriegel Alison J , Cowley Allen W , Liang Mingyu
Published: April 2024

Chronic kidney disease (CKD) puts patients at a greatly increased risk of cardiovascular disease in a condition termed chronic renocardiac syndrome (RCS). We have utilized the 5/6 nephrectomy (5/6 NX) model in Sprague Dawley rats to study the gradual development of cardiac dysfunction resulting from declining kidney function. Previously, we identified alterations in several microRNAs (miRNAs) in left ventricle (LV) tissue 7 weeks after 5/6 NX surgery. We hypothesized that the upregulation of miR-21 in the LV following 5/6 NX contributes to LV pathology, rather than being a consequence of it. In situ hybridization revealed that miR-21 expression in the LV of 5/6 NX animals is highest in regions of perivascular fibrosis. To study the impact of miR-21 on LV remodeling and function, we delivered locked-nucleic acid (LNA) modified anti-miR-21 or anti-scrambled-miR (Exiqon, delivered i.v. at 1 mg/kg) to 5/6 NX animals (n=6/group) in 3 sequential days at 1 week post-surgery, and again 4 weeks post-surgery. Echocardiography was performed prior to 5/6 NX surgery and bi-weekly thereafter, throughout the 7 week study, to evaluate remodeling and function (anti-miR-21 vs. anti-scramble treated for all comparisons). The average LV miR-21 expression was reduced nearly 12-fold with anti-miR-21 treatment when measured 7 weeks post-5/6 NX. Anti-miR-21 treatment preserved stroke volume and fractional shortening between weeks 3 and 5 post-5/6 NX while both functional indices declined in anti-scramble treated rats. Additionally, concentric LV remodeling (LV wall hypertrophy and reduced chamber diameter) 5 weeks post-5/6 NX was completely prevented with anti-miR-21 treatment. At 7 weeks post-5/6 NX, when LV decompensation is evident in untreated rats, anti-miR-21 treatment maintained LV wall thickness and chamber diameter while fractional shortening was significantly increased (p <0.05). Anti-miR-21 treatment had no effect on blood pressure. We conclude that chronic knockdown of miR-21 in the 5/6 NX model prevented pathological concentric remodeling. Together these data suggest that the upregulation of cardiac miR-21 following 5/6 NX is an important mediator of pathological cardiac remodeling and dysfunction.
Abstract 18072: Low Endothelial Shear Stress is Associated With High-Risk Coronary Plaque Characteristics in Humans: A Three-Dimensional Frequency-Domain Optical Coherence Tomography Study
Authors: Vergallo Rocco , Papafaklis Michail I , Jia Haibo , Bourantas Christos V , McNulty Iris , Lee Hang , Yu Bo , Porto Italo , Biasucci Luigi M , Crea Filippo , Feldman Charles L , Michalis Lampros K , Stone Peter H , Jang Ik-Kyung
Published: April 2024

Introduction:
Large lipid pool and thin fibrous cap are characteristics of plaques at high-risk for rupture resulting in adverse cardiac events. However, the local factors associated with the development of a rupture-prone plaque phenotype are not well known in humans. Endothelial shear stress (ESS) plays a major role in the development and progression of atherosclerotic plaques. We sought to investigate in vivo the relationship between computed ESS and plaque characteristics assessed by frequency-domain optical coherence tomography (FD-OCT).

Methods:
Three-dimensional coronary artery reconstruction was performed in 9 patients (4 left anterior descending, 2 left circumflex and 3 right coronary arteries) presenting with acute coronary syndrome using FD-OCT and coronary angiography. Each coronary artery was divided into sequential 3-mm segments, and each segment was analyzed for the assessment of predominant local ESS value by computational fluid dynamics and morphologic characteristics by FD-OCT. A total of 58 non-culprit segments without significant stenosis were evaluated.

Results:
Segments with low ESS (<1 Pascal [Pa]) had significantly larger lipid arc (120.9° ± 36.2° vs. 82.5° ± 22.0°, p = 0.015) and thinner fibrous cap (172.7 ± 69.4 μm vs. 264.5 ± 110.5 μm, p = 0.008) compared to segments with higher ESS (≥1 Pa) (Figure). Segments with macrophage accumulation tended to have lower local ESS values (0.98 ± 0.42 Pa vs. 1.62 ± 1.50 Pa, p = 0.170) compared to those without macrophage accumulation. Similarly, segments with lipid-rich plaque (lipid arc >90°) showed lower ESS values compared to those without lipid-rich plaque (1.06 ± 1.02 Pa vs. 1.78 ± 1.54 Pa, p = 0.177).

Conclusions:
The present study shows that coronary regions exposed to low ESS are characterized by larger lipid burden and thinner fibrous cap, suggesting that low ESS has a critical role in the development of vulnerable plaques.
Abstract 18123: An Integrated Resuscitation Service, Combining a Specialist Pre-Hospital Physician Response Unit With Delivery to a Dedicated High-Volume Cardiac Arrest Centre, Optimises Survival Following Cardiac Arrest
Authors: Akhtar Mohammed M , Hunter-Dunn Ceri , Weaver Anne , Rees Paul
Published: April 2024

Background:
Despite advances in resuscitation medicine, survival rates to discharge following out-of-hospital cardiac arrest (OHCA) remain poor. Recent data support early critical care interventions including therapeutic hypothermia (TH) and immediate percutaneous coronary intervention (PCI). In London, a package of high quality physician-led critical care intervention on scene, with the capacity to transfer these patients direct to a PCI centre, is available through the deployment of London’s Air Ambulance specialist Physician Response Unit (PRU).

Methods:
Prospective data was gathered on OHCA treated by the PRU, which were transferred to a single PCI centre. Data included patient demographics, clinical characteristics, interventions and outcome.

Results:
Between April 2011 and April 2013, data was obtained on 20 patients, with a mean age of 59. Clinical characteristics - presenting rhythm: VF 65%, asystole 15%, PEA 15%, VT 5%. Return of spontaneous circulation (ROSC) was achieved at scene in 75%. PRU interventions: Advanced airway management 90%, rapid sequence induction 50%, early TH 45%, mechanical CPR (mCPR) during transfer 15%. Overall survival to ICU was 50%, with overall survival to discharge 45%. Of those patients who underwent emergency angiography, 71% survived to ICU, with 64% surviving to discharge. Of patients presenting in VF, 62% survived to discharge. Interestingly, 66% of patients who received TH survived to discharge, compared with 45% where TH was not used. All patients who underwent successful PCI survived to discharge with good neurological outcomes.

9 patients had a confirmed single vessel culprit lesion treated by PCI, one patient had complex mutlivessel disease complicated by cardiogenic shock and underwent mutivessel PCI, and 2 patients had an undiagnosed underlying cardiomyopathy.

Conclusions:
In selected cases, outcomes following OHCA can be optimized by integrating a PRU cardiac arrest service, enabling direct triage of patients to a cardiac arrest centre, with early application of neuroprotective strategies, mCPR, circulatory support and interventional cardiology techniques.
Abstract 18125: Left Ventricular Radial Strain Improvement After Surgery for Ebstein’s Anomaly
Authors: Pinyoluksana Krong-on , Kane Garvan , Eidem Benjamin , Villarraga Hector , Dearani Joseph , Connolly Heidi , Ammash Naser
Published: April 2024

Background:
Impact of right ventricular (RV) overload on left ventricular (LV) performance has been demonstrated in Ebstein’s anomaly (EA). We have shown that LV radial strain (RS) in 83 EA patients was significantly less than in controls. We subsequently sought to evaluate LV strain after EA surgery.

Methods:
Systolic strain, strain rate (SR) and early diastolic strain rate (SRe) were retrospectively performed, using velocity vector imaging, in 24 repaired EA patients (age 35 ±12 years; 67% women) with LV ejection fraction >50%, preoperatively (median 5 days [1-145 days]) and postoperatively within 5 years at sequential follow-up (6 months-3 years). Repair of EA included tricuspid valve repair, valve replacement and bidirectional cavopulmonary anastomosis. A slope of change postoperatively was estimated for each subject using linear regression. A one-sample t-test of the mean slope=0 assessed average change per year.

Results:
Mean (standard deviation) and median (range) of preoperative LV RS was 36.5 +/- 11.4% and 36.3% (16.8-59.8) respectively. LV strain analyses are summarized in tables 1 and 2.

Conclusions:
LV RS improved significantly after EA surgery whereas circumferential strain (CS), SR and radial SR did not. This may reflect the change in RV and subsequently LV geometry after resolution of tricuspid regurgitation with EA surgery. Ongoing evaluation with deformational imaging may help to characterize if these changes are compensatory or maladaptive and may determine optimal timing for surgery. In the subgroup with the lowest RS, significant improvement postoperatively was not seen. This may suggest that surgery was performed too late to allow favorable remodeling.
Abstract 18155: Wnt10b Promotes Cardiac Functional Recovery After Infarction Through Stimulation of Coronary Vessel Formation and Cardiomyogenesis
Authors: Paik David T , Rai Meena , Ryzhov Sergey , Feoktistov Igor , Hatzopoulos Antonis K
Published: April 2024

We previously showed that the canonical Wnt signaling ligand Wnt10b is strongly induced in mouse hearts one week after infarction during the initial stages of cardiac tissue repair. Wnt10b regulates cell fate decisions in various organs, but its role in the heart is unknown. Using histological and molecular analyses, we discovered that Wnt10b is normally expressed in cardiomyocytes and stored in the intercalated discs. One week after coronary artery ligation, Wnt10b is strongly and specifically induced in cardiomyocytes surrounding the infarct zone. To determine the role of Wnt10b in cardiac repair, we generated a new mouse transgenic line to enhance the levels of endogenous Wnt10b expression in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the infarct zone, reduced scar size, and improved ventricular function compared to wild-type mice. Wnt10b stimulated Vascular Endothelial Growth Factor Receptor 2 (Vegfr-2) in endothelial cells and Angiopoietin-1 in smooth muscle cells through NF-kB activation. These effects coordinated endothelial growth and pericyte recruitment, thus promoting the formation of large, coronary-like blood vessels. Enhanced neovascularization and reduced fibrosis was accompanied by formation of cardiomyocyte islands within scar tissue, suggesting that Wnt10b promoted myocardial regeneration. Taken together, our results indicate that Wnt10b is a physiological regulator of coordinated formation of blood vessels and myocardial regeneration in the injured heart. Our findings could lead to novel effective strategies to optimize the inherent reparative and regenerative capacities of the heart in order to prevent the onset of heart failure after myocardial infarction.
Abstract 18168: Plasma Free Fatty Acids, Fatty Acid-Binding Protein 4, and Mortality in Older Adults in the Cardiovascular Health Study
Authors: Miedema Michael D , Maziarz Marlena , Biggs Mary Lou , Zieman Susan J , Kizer Jorge R , Ix Joachim H , Mozaffarian Dariush , Tracy Russell , Psaty Bruce M , Siscovick David , Mukamal Kenneth J , Djousse Luc
Published: April 2024

Background:
Plasma free fatty acids (FFA) are important in energy homeostasis and fatty acid-binding protein 4 (FABP4) is a key cytoplasmic chaperone of fatty acids. While both FFA and FABP4 have been associated with cardiovascular risk factors and cardiovascular events, limited and inconsistent data are available on the relation of these biomarkers with cardiovascular and total mortality.

Methods and Results:
We studied 4,707 participants with plasma FFA and FABP4 measured at baseline (1992-1993) in the Cardiovascular Health Study. The mean age of the participants was 75 (range 64-98) and 58.3% were women. Over a median follow-up of 11.8 years, 3,555 of the participants died. Cox proportional hazard models were used to estimate hazard ratios (HR) for mortality. After adjustment for age, sex, race, clinic, education, body-mass index, cystatin c, albumin, physical activity, alcohol intake, smoking, hormone replacement therapy in women, self-reported health status, systolic blood pressure, LDL cholesterol, HDL cholesterol, hypertensive medication, and lipid-lowering medication, FFA (HR: 1.14, 95% CI 1.09-1.18 per SD [0.2 mEq/L] higher FFA) but not FABP4 (HR: 1.04 (95% CI: 0.98-1.09 per SD [18.9 ng/mL] higher FABP4) levels were associated with total mortality. In a cause-specific mortality analysis, higher concentrations of FFA were associated with a greater risk of death due to cardiovascular and certain non-cardiovascular causes (Table 1).

Conclusion:
In a cohort of community-dwelling older individuals, elevated plasma concentrations of FFA (but not FABP4) were associated with cardiovascular and non-cardiovascular mortality.
Abstract 18169: Identifying Early Changes in Myocardial Microstructure via Ultrasound in Hypertensive Heart Disease
Authors: Hiremath Pranoti , Bauer Michael , Cheng Hui-Wen , Unno Kazumasa , Patel Ravi , Harvey Bethany , Liao Ronglih , Cheng Susan
Published: April 2024

BACKGROUND:
The transition from healthy myocardium to hypertensive heart disease is characterized by a series of poorly understood changes in myocardial tissue microstructure. Incremental alterations in the orientation and deformation of myocardial fibers can now be assessed using advanced techniques in ultrasonic image analysis.

METHODS:
We used a modified approach to non-invasively assess left ventricular (LV) myocardial microstructure, based on sonographic signal intensity analysis of the inferolateral pericardium (viewed in the parasternal long-axis view of B-mode echocardiographic images). We defined the transmission intensity (TI), an indirect measure of the intensity reflection coefficient at the myocardial-pericardial interface, as 1 - (P/256) where P is the 25th percentile value of pericardial signal intensity on a 256 scale. We determined the extent to which TI is able to differentiate between normal myocardium and hypertensive heart disease in a mouse model and in humans.

RESULTS:
As shown in the Figure, 7-week echocardiographic measurements of TI were significantly different between groups of mice that underwent fixed aortic banding (n=3) versus sham procedure (n=3) at baseline. Similarly, measurements of TI were significantly different between individuals with uncomplicated essential hypertension (N=30, age 54±3 yrs, 47% women) and healthy controls (N=28, age 53±9 yrs, 60% women). Although there was a trend in higher relative wall thickness in hypertensive individuals compared to controls (P=0.09), there was no difference between these groups in LV mass (P=0.67) or LV wall thickness (P=0.26).

CONCLUSION:
Based on sonographic signal intensity analysis, the TI is an accessible, non-invasive measure that appears to differentiate normal LV microstructure from myocardium exposed to chronic afterload stress. The TI may be a particularly sensitive measure of myocardial changes that occur early in the course of disease progression.
Abstract 18179: Prognostic Markers of Left Ventricular Dysfunction in Patients With Newly Recognized Cardiomyopathy and Atrial Fibrillation
Authors: Patel Shalin J , Shah Sachin , Goldman Alena , Josephson Mark E , Zimetbaum Peter J
Published: April 2024

INTRODUCTION:
Tachycardia-induced cardiomyopathy (TIC) is confirmed with the improvement in ventricular function following restoration of sinus rhythm or control of ventricular rate. We sought to identify characteristics which could predict recovery of left ventricular dysfunction (LVD) in patients who present with newly recognized cardiomyopathy and atrial fibrillation (AF).

METHODS:
114 consecutive patients presenting for cardioversion to our institution with newly recognized LVD defined as LVEF ≤ 45% and AF were identified. Patients with known cardiomyopathy, without admission ECG or follow up echocardiogram were excluded. QRS duration from admission ECG was used as a binary variable (≥ 125 ms or < 125 ms) while LVEDD from admission echocardiogram was used as a binary variable (≥ 5.6 cm or < 5.6 cm). The outcome was a binary variable, resolution of cardiomyopathy (LVEF ≥ 45%) or persistence of cardiomyopathy (LVEF ≤ 45%). The outcome was analyzed with logistic regression model using STATA. The outcomes were adjusted for age, gender, obstructive sleep apnea, coronary artery disease, diabetes mellitus, hypertension, excessive alcohol ingestion, tobacco, beta blockers, ACE inhibitors and aldosterone antagonist.

RESULTS:
92 patients met the inclusion and exclusion criteria. Possible TIC was diagnosed in 65 patients who had recovery of LVD. Mean QRS duration in patients with possible TIC was 101 +/- 18 ms while LVEDD was 5.21 +/- 0.67 cm. In patients with persistent LVD, mean QRS duration was 120 +/- 27 ms while LVEDD was 5.61 +/- 1.0 cm. Normal QRS duration (< 125 ms) on admission ECG was associated with a significantly higher incidence of LV functional recovery (adjusted odds ratio: 4.02; 95% CI: 1.21 - 13.33, p = 0.023). Normal LVEDD (<5.6 cm) on presentation was also associated with a significantly higher incidence of LV function recovery (adjusted odds ratio: 3.75; 95% CI: 1.43 - 9.85, p = 0.007).

Next Step/Future:
Normal QRS duration on admission ECG and LVEDD on admission echocardiogram in patients presenting with newly diagnosed AF and cardiomyopathy serve as good markers of LV function recovery. If confirmed by larger prospective series, QRS duration and LVEDD on presentation can be used as prognostic markers in patients with new onset AF and cardiomyopathy.
Abstract 18191: Mitochondrial Regulation of the Hyperproliferative Vascular Smooth Muscle Cell Phenotype
Authors: Salabei Joshua K , Jones Steven P , Bhatnagar Aruni , Hill Bradford G
Published: April 2024

Background:
During arterial restenosis and atherosclerosis, vascular smooth muscle cells (VSMCs) develop a highly proliferative and synthetic phenotype. Because such phenotypic changes are likely integrated with the energetic state of the cell, we hypothesized that changes in mitochondrial function regulate VSMC plasticity.

Methods and Results:
Exposure of VSMCs to platelet-derived growth factor (PDGF) promoted loss of the contractile proteins α-smooth muscle actin and calponin and was accompanied by remarkable changes in mitochondrial morphology. Confocal analysis showed that 97% of mitochondria in contractile VSMCs were filamentous; however, synthetic VSMCs showed a mitochondrial pool with >70% fragmented mitochondria (p<0.05). Mitochondrial membrane potential decreased by 86±1% with the attainment of the synthetic phenotype (p<0.01; n=3), but was not associated with mitophagy or decreases in the abundance of key proteins involved in oxidative phosphorylation. Compared with contractile VSMCs, synthetic VSMCs showed a 51±1.9% decrease in the abundance of mitofusin 2 (Mfn2; p<0.001; n=3) with no significant changes in Drp1, Fis1, or Opa1. Analysis of mitochondrial function in intact VSMCs showed a 20±3.7% decrease in glucose oxidation in synthetic cells, which was accompanied by a 17±2.6% increase in fatty acid oxidation (p<0.02; n=3). In permeabilized cells, complex II-mediated respiration was decreased by 20±2% in synthetic VSMCs (p<0.05; n=4). An inhibitor of mitochondrial fragmentation, mdivi1, decreased mitochondrial fragmentation by 50±6% (p<0.001; n=3), abolished the hyperproliferative response to PDGF (p<0.03; n=4), and reversed changes in mitochondrial respiration, yet it did not prevent PDGF-induced losses of contractile proteins.

Conclusions:
These results indicate that changes in mitochondrial morphology and bioenergetics contribute to the hyperproliferation of synthetic VSMCs, but do not affect the degradation of the contractile proteins. We propose that mitochondrial fragmentation that occurs during transition to the synthetic phenotype regulates mitochondrial substrate selection and bioenergetics and is a therapeutic target for vascular disorders characterized by VSMC hyperproliferation.
Abstract 18201: Src-Dependent Caveolar Trafficking Defects in Hereditary Pulmonary Arterial Hypertension
Authors: Prewitt Allison R , Ghose Sampa , Frump Andrea , Kenworthy Anne , de Caestecker Mark
Published: April 2024

Patients with hereditary pulmonary arterial hypertension (HPAH) inherit heterozygous germ line mutations in the BMP type 2-receptor, BMPR2, but it is not known how these mutations cause the disease. Bmpr2 mutant mice have endothelial dysfunction and increased vascular permeability, and are more susceptible to the development of pulmonary hypertension. In these studies we explore the mechanisms mediating endothelial barrier dysfunction in Bmpr2+/- mice. Conditionally immortalized pulmonary endothelial cells (ciPECs) from Bmpr2+/- mice have increased permeability to 70kD dextran and albumin, but not to 4kD dextran, suggesting that Bmpr2+/- ciPECs have intact cell-cell junctions but increased transcellular (vesicle mediated) permeability. Caveolae are the predominant vesicle involved in transcellular permeability in endothelium. Transmission EM shows an increase in Caveolar structures in ciPECs and intact endothelium of Bmpr2+/- lungs. Quantitative analysis indicates that Caveolin-1 (Cav1) and Cavin have altered localization from the plasma membrane (PM) in wild type ciPECs to an intracellular localization in Bmpr2+/- ciPECs. In addition, inhibition of Caveolar endocytosis with the Dynamin-2 inhibitor, Dynasore, restores Cav1 localization to the PM in Bmpr2+/- PECs, suggesting there is increased Dynamin-dependent Caveolar endocytosis and trafficking in Bmpr2+/- ciPECs. Bmpr2+/- ciPECs also have increased levels of phosphorylated (pY14) Cav1 associated with increased expression of active Src-kinase (pY416), the kinase responsible for phosphorylating Cav1 and initiating Caveolar endocytosis. The selective Src-family kinase inhibitor PP2, reduces pY14-Cav1 and rescues Cav1 and Cavin localization to the PM in Bmpr2+/- ciPECs. Furthermore, PP2 restores endothelial barrier function in Bmpr2+/- ciPECs demonstrated by a reduction in albumin and 70kD dextran permeability. These data demonstrate a defect in Caveolar trafficking mediated by constitutive activation of Src kinase in Bmpr2+/- ciPECs, and suggest Src kinase inhibitors may ameliorate endothelial barrier dysfunction in HPAH patients.
Abstract 18204: Activation of the Pro-Hypertrophic Calcineurin/Nfat-Pathway Mediates Atrio-Ventricular Conduction Disturbances in Cardiac Sodium Channelopathy
Authors: Rivaud Mathilde , Wolswinkel Rianne , Baartscheer Antonius , van der Made Inge , van Rijen Harold V , Bezzina Connie R , Creemers Esther E , Remme Carol Ann
Published: April 2024

Introduction:
SCN5A mutations have been associated with progressive atrio-ventricular conduction disturbances and development of cardiac structural abnormalities. In transgenic Scn5a-1798insD+/- mice, intracellular sodium and calcium concentrations are increased, setting the stage for potential activation of calcium-dependent signaling pathways. Here we investigated the impact of the pro-hypertrophic calcineurin/Nfat signaling pathway on atrio-ventricular (AV) conduction in Scn5a-1798insD+/- mice.

Methods and Results:
Aged (12-18 months old) Scn5a-1798insD+/- (MUT) mice developed cardiac hypertrophy (increased heart weight and Anf mRNA levels) and progressive AV-conduction abnormalities on surface ECG. Isolated Langendorff-perfused aged MUT hearts showed profound AV-delay and AV-block at high right atrial stimulation frequencies (basic cycle length 90-120 ms). To study the contribution of the calcineurin/Nfat signaling pathway to the AV-conduction phenotype, adult (age 3-5 months) wild-type (WT) and MUT mice were subjected to 2 weeks of transverse aortic constriction (TAC). WT and MUT mice showed similar hypertrophic responses to TAC. However, MUT-TAC mice displayed increased PR-interval on surface ECG and a higher incidence of sudden death. Furthermore, isolated MUT-TAC hearts showed AV-block and significantly prolonged AV-delay as compared to WT-TAC or sham hearts. Atrial and His-ventricular conduction was unaffected in MUT-TAC hearts, indicating that conduction delay occurred within the AV-nodal region. Since Nfatc2 is a well-described downstream effector of the calcineurin pathway, adult MUT mice were crossed with mice lacking Nfatc2 (Nfatc2-KO). In MUT/Nfatc2-KO hearts, AV-delay after TAC was attenuated as compared to MUT-TAC, indicating rescue of the AV-conduction disturbances by Nfatc2 deficiency.

Conclusions:
Scn5a-1798insD+/- mice develop profound atrio-ventricular conduction disturbances with increased age and after activation of the calcium-dependent pro-hypertrophic calcineurin/Nfat-pathway. These findings indicate that cardiac hypertrophy may modulate disease severity in cardiac sodium channelopathy.
Abstract 18212: Unique Exonic RNA Polymerase II Pausing in the Hypoxia Inducible Factor-1 Alpha Gene is Associated With Alternative Splicing
Authors: Shin Hyewon , Toli Jessica , He Minzhen , Sayed Danish , Abdellatif Maha
Published: April 2024

Hypoxia-inducible factor 1α (Hif-1α) is the primary transcription factor that promptly increases upon exposure of the cells to hypoxia. It is mainly regulated by posttranscriptional and posttranslational mechanisms involving miR-199a and prolyl hydroxylase, respectively. In addition, the discovery of multiple Hif-1α isoforms suggests that alternative splicing may play a role in regulating its activity, although little is known about this in the heart. We, thus, hypothesized, that in addition to the known mechanisms, Hif-1α is activated by an alternative splicing step, a process that is tightly coupled to transcription. To test this, we treated myocytes with antimiR-199a, which robustly induces Hif-1α expression, and analyzed its effects on gene transcription using RNA polymerase II Chromatin immunoprecipitation-deep sequencing. The analysis revealed that antimiR-199a induced 1) the upregulation of genes that are predominantly Hif-1α targets including Pdk1, Glut3, Vegfa, Bnip3, Ndrg1, and Gys1, in addition to Pfkm, G0s2 and Sdpr, which are a subject of an independent study, and 2) a unique, very precise RNA pol II pausing (accumulation of pol II at a very precise sites with a density >2x of its flanking sequence) within the exons of only the Hif-1α gene, while RNA pol II at the transcription start site, and within other regions of the gene body, was similar to the control myocytes. In particular, all exons except for exons 1, 10, and 11, exhibited some degree of pausing, where exon 15 had a pol II pausing peak that was 20 fold higher than the flanking pol II density. Deceleration of transcriptional elongation has been associated with RNA splicing, however, these very precise exonic pausing peaks are quite unique. Using quantitative PCR, were able to confirm that during normoxia, Hif-1α was abundant as determined by primers specific for exons 10, 11, and 12, which increased by ~2 folds with miR-199a treatment. On the other hand, exon 15, which encodes part of the transactivation domain, was relatively lower during normoxia but increased 300x with antimiR-199a treatment. The result suggests that alternative splicing of exon 15 is a critical regulatory step required for the transcriptional activity of Hif-1α, which is associated with the increase in its protein.
Abstract 18239: Microrna-204 and -486 Regulate the Expression of Osteogenic Transcription Factors in Human Aortic Valve Cells: Evidence for Epigenetic Modulation of Valvular Cell Osteogenic Reprogramming
Authors: Song Rui , Fullerton David A. , Ao Lihua , Zhao Kesen , Meng Xianzhong
Published: April 2024

Calcific aortic valve disease affects a large number of elderly people. Aortic valve interstitial cells (AVIC) play an important role in valvular calcification. However, pharmacological prevention of the progression of this disease is unavailable due to limited knowledge of underlying molecular mechanisms. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) are capable of inducing AVIC reprogramming (expression of osteogenic transcription factors) and have been implicated in the pathogenesis of calcific aortic valve disease. We hypothesized that microRNAs modulate the responses of human AVIC to TGF-β1 and BMP-2 stimulation.

Methods and results:
Stimulation of AVIC isolated from normal human aortic valves with TGF-β1 or BMP-2 up-regulated the expression of osteogenic transcription factors Runx2 and Osx. Prolonged stimulation with TGF-β1 or BMP-2 induced calcium deposit formation. MicroRNA array and real-time qRT-PCR analysis revealed that TGF-β1 and BMP-2 each down-regulated microRNA-204 and up-regulated microRNA-486. MicroRNA-204 mimic suppressed the expression of Runx2 and Osx, and microRNA-204 inhibitor increased Runx2 and Osx levels in cells exposed to TGF-β1 or BMP-2. Conversely, microRNA-486 mimic increased Runx2 and Osx levels, and microRNA-486 inhibitor reduced Runx2 and Osx expression in cells exposed to TGF-β1 or BMP-2. More importantly, treatment of human AVIC with a combination of microRNA-204 inhibitor and microRNA-486 mimic up-regulated the expression of Runx2 and Osx, and induced calcium deposit formation in the absence of TGF-β1 or BMP-2.

Conclusions:
TGF-β1 and BMP-2 induce the expression of Runx2 and Osx in human AVIC that is associated with down-regulation of microRNA-204 and up-regulation of microRNA-486. MicroRNA-204 negatively, but microRNA-486 positively modulates Runx2 and Osx expression in human AVIC, and microRNA-204 inhibitor and microRNA-486 mimic synergistically promote human AVIC osteogenic reprogramming. These findings provide new insight into the mechanism by which TGF-β1 and BMP-2 promote aortic valve calcification and indicate that microRNAs are potential therapeutic targets for suppression of the progression of calcific aortic valve disease.
Abstract 18311: Lipid Composition of Gold Nanoparticle-Templated High-Density Lipoprotein Analogs Dictates Cholesterol Efflux Function
Authors: Mutharasan R. Kannan , Singh Amritha T , McMahon Kaylin M , Thaxton C. Shad
Published: April 2024

Background:
Reverse cholesterol transport, the process by which cholesterol is effluxed from cells to high-density lipoproteins (HDL) and is delivered to the liver for clearance, is a promising pathway to augment for treatment of atherosclerosis. Though structure-function relationships between nascent, discoidal HDL and cholesterol efflux have been well studied, how the lipid composition of spherical HDL species, which varies in pathophysiological conditions, impacts their ability to mediate cholesterol efflux has not been investigated.

Methods and Results:
Spherical gold nanoparticles (5 nm) were used to synthesize spherical HDL analogs (HDL-NP) by adding ApoAI protein and various lipids to the particle surface. With this strategy a panel of HDL-NP varying in lipid content was generated. HDL-NP designs tested include: dipalmitylphosphatidylcholine (DPPC, saturated fatty acid), dioleoylphosphatidylcholine (DOPC, unsaturated fatty acid), sphingomyelin, lysophosphatidylcholine (LPC), and mixtures thereof. All of these lipids are found in natural HDL. After characterizing the purified HDL-NP, these HDL-NP designs were tested in the cellular reverse cholesterol transport assay using J774 mouse macrophages. These studies demonstrate that all HDL-NP designs mediate more efflux than equimolar amounts of ApoAI protein control, and further demonstrate that HDL-NP designs incorporating unsaturated phospholipid (DOPC), sphingomyelin, and LPC--each of which can increase disorder in the lipid membrane and thus give rise to opportunity for cholesterol to intercalate and bind--enhance cholesterol efflux compared to the saturated phospholipid (DPPC) design.

Conclusion:
In summary, these results demonstrate that lipid content of HDL-NP,analogs of spherical HDL, dictates cholesterol efflux function, a finding which sheds light on the functional importance of lipid content variation seen in mature, spherical HDL species.