bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17499: Addition of Myocardial Parameters to the Diagnosis of Stage B Heart Failure
Authors: Marwick Tom , Kosmala Wojciech , Jellis Christine
Published: July 2021

Introduction:
Stage B heart failure (BHF, asymptomatic structural heart disease) is diagnosed in the presence of myocardial scar or impaired LVEF. However, the insensitivity of LVEF may lead to under-recognition of BHF in non-ischemic heart disease. This may be important, as BHF may precede the onset of HF symptoms, and necessitates the initiation of treatment. We sought the implications of using additional LV assessment to identify BHF in pts at risk of HF (stage A HF, AHF).

Methods:
We studied 510 asymptomatic pts (age 58±12yrs) with AHF (diabetes, hypertension or obesity), but no history of ischemic heart disease and a normal stress echo. All pts underwent echocardiography (including assessment of strain and diastolic dysfunction) and cardiopulmonary exercise testing.

Results:
BHF was defined as the presence of at least one of; reduced LV longitudinal strain (<18%), increased LV filling pressure (E/e’>13) or moderate-to-severe LV hypertrophy (LV mass index ≥109 g/m
2
in women and 132 g/m
2
in men) in 243 patients (47%). Reduced exercise capacity (peakVO
2
and METS) was identified in BHF compared with other AHF (Table). Using this definition, BHF was associated with lower peak VO
2
(β=-0.20, p<0.00001) and METS (β=-0.21, p<0.0001), independent of higher BMI, insulin resistance, older patient age, male sex and treatment with beta-blockers.

Conclusions:
LV hypertrophy, elevated LV filling pressure elevation and abnormal myocardial deformation independently contribute to lower exercise capacity in pts at risk of HF. Given the association of exercise capacity with outcome, these factors should be considered grounds for the diagnosis of BHF.
Abstract 17514: Hydrogen Sulfide Levels and NRF2 Activity are Attenuated in the Setting of Critical Limb Ischemia (CLI)
Authors: Islam Kazi N , Polhemus David J , Donnarumma Erminia , Otsuka Hiroyuki , Bhushan Shashi , Bradley Jessica M , Cirino Giuseppe , Luke Brewster P , Lefer David J
Published: July 2021

Background:
Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythriod 2-related factor 2 (NRF2) is responsible for the expression of antioxidant response element (ARE)-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S producing enzymes, H2S, and NRF2 activation status in skeletal muscle obtained from CLI patients.

Methods:
Gastrocnemius tissues were attained post amputation from human CLI and aged-matched control patients. Tissue H2S levels were measured using gas chromatography methods coupled with sulfur chemiluminescence. RT-qPCR, immunoblot, and electrophoretic mobility shift assay (EMSA) were used to analyze respective gene expression, protein levels, and DNA binding activity, respectively.

Results:
We found mRNA and protein levels of CSE, CBS, and 3-MST were significantly decreased in skeletal muscle of CLI (~2 fold, p < 0.05) patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in NRF2 activation (2 fold, p < 0.05) as well as antioxidant proteins, such as CuZn-superoxide dismutase (2 fold, p < 0.05), catalase (2 fold, p < 0.05), and glutathione peroxidase (2 fold, p < 0.05) in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation were significantly increased (2 fold, p < 0.05) in skeletal muscle of CLI patients as compared to age-matched controls.

Conclusions:
The data demonstrate that H2S bioavailability and NRF2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S producing enzymes may contribute to the pathogenesis of CLI.
Abstract 17520: Emerging Prognostic Factors in Patients with Aortic Stenosis -A Report from the CHART-2 Study
Authors: Sato Kenjiro , Sakata Yasuhiko , Nochioka Kotaro , Miyata Satoshi , Miura Msanobu , Tadaki Soichiro , Ushigome Ryuichi , Yamauchi Takeshi , Onose Takeo , Tsuji Kanako , Abe Ruri , Shimokawa Hiroaki
Published: July 2021

Introduction:
Along with the rapid aging of general population, the prevalence of aortic stenosis (AS) has also been increasing worldwide, especially in the developed countries including Japan. The previous studies showed that NYHA class and the severity of AS are the major classical prognostic factors (e.g. valve anatomy, valve hemodynamics). However, since AS is one of the major degenerative diseases of the elderly, it is conceivable that other prognostic factors are also involved in the current practice of AS.

Methods:
We examined the prognostic factors for 3-year mortality of 412 consecutive AS patients (mean age 74.9 years, male 52.4%), defined as peak pressure gradient ≥30mmHg, among 10,219 patients with stage B/C/D heart failure (HF) registered in CHART-2 Study (N=10,219).

Results:
The prevalence of NYHA I, II, III and IV was 37.7%, 50.9%, 10.8%, and 0.7%, respectively. Renin-angiotensin system inhibitors, beta-blockers, and diuretics were prescribed in 66.7%, 26.9%, and 64.6%, respectively. Crude 3-year mortality was 9.5%, 16.5%, and 49.7% in patients with NYH class I, II and III/IV, respectively (PIII, aortic peak flow (APF)>4.5m/s, serum albumin (Alb), chronic kidney disease (CKD) and use of diuretics was the best model to predict the mortality of AS patients (Table).

Conclusions:
The present study demonstrates that in addition to NYHA class and APF, other factors (age, sex, HR, Alb, CKD, and use of diuretics) could also be associated with mortality of AS patients, suggesting that these new factors should also be taken into consideration when evaluating long-term prognosis of AS patients in the current era.
Abstract 17534: Afferent Vagal Nerve Stimulation Dose Dependently Inhibits Sympathetic Nerve Activity Through the Resetting of Baroreflex Central Arc
Authors: Oga Yasuhiro , Kishi Takuya , Saku Keita , Kakino Takamori , Nishizaki Akiko , Fujii Kana , Arimura Takahiro , Ikeda Masataka , Ide Tomomi , Sunagawa Kenji
Published: July 2021

Background:
Arterial baroreflex is a powerful regulator of the sympathetic nerve activity (SNA) and arterial pressure (AP). Although vagal nerve stimulation (VNS) has been developed as a neuro-modulatory therapy for heart failure, the impact of VNS on baroreflex and SNA remains unknown. Since the afferent fibers of vagal nerves and of baroreceptors converge in the nucleus tractus solitarii, we investigated how the selective afferent VNS (AVNS) impacts on baroreflex in regulating SNA and AP.

Methods:
We used 6 anesthetized Sprague-Dawley rats (530±11g). We vascularly isolated bilateral carotid sinuses and servo-controlled intra-sinus pressure (CSP). We measured AP, CSP and splanchnic SNA simultaneously. We attached an electrode to the vagal nerve. We established the baseline intensity (voltage) of VNS that reduced heart rate by 10-20%. We then sectioned the vagal nerve at the caudal side of the electrode. We conducted AVNS at 3 doses, baseline, 2xbaseline and 4xbaseline. We changed CSP stepwise from 60 to 160mmHg to analyze static baroreflex function with/without AVNS. To estimate dynamic baroreflex function, we perturbed CSP using binary random sequence (mean AP±20mmHg) and compared the transfer functions (TF) with/without AVNS.

Results:
AVNS dose-dependently shifted the CSP-SNA relation downward (p<0.05, Fig. 1) without changing the maximum gain, while did not affect the SNA-AP relation (Fig. 2). The TF of CSP-SNA relation approximated a high pass filter characteristics. AVNS dose-dependently decreased the dynamic gain (Control: 0.72±0.20, baseline: 0.46±0.14, 2xbaseline: 0.38±0.12, 4xbaseline: 0.20±0.08 %/mmHg, p<0.05), whereas did not affect the TF of SNA-AP relation.

Conclusions:
AVNS dose-dependently suppresses SNA by resetting the static CSP-SNA relation, i.e., the baroreflex central arc. However, AVNS reduces the dynamic gain of baroreflex central arc. We conclude that AVNS lowers SNA at the expense of compromising dynamic AP stabilization.
Abstract 17557: Prevalence, Characteristics, and Early Treatment Strategies of Patients with Chronic Total Occlusions Undergoing Coronary Computed Tomography Angiography
Authors: Opolski Maksymilian P , Hartaigh Bríain Ó , Gransar Heidi , Schulman-Marcus Joshua , Truong Quynh A , Berman Daniel S , Budoff Matthew J , Achenbach Stephan , Al-Mallah Mouaz , Andreini Daniele , Cademartiri Filippo , Callister Tracy Q , Chang Hyuk-Jae , Chinnaiyan Kavitha , Chow Benjamin J , Cury Ricardo , Delago Augustin , Hadamitzky Martin , Hausleiter Joerg , Feuchtner Gudrun , Kim Yong-Jin , Kaufmann Philipp A , Leipsic Jonathon , Lin Fay Y , Maffei Erica , Pontone Gianluca , Raff Gilbert , Shaw Leslee J , Villines Todd C , Dunning Allison , Min James K
Published: July 2021

Introduction:
Data describing the prevalence, characteristics, and management of chronic total occlusions (CTO) in patients undergoing coronary computed tomography angiography (CCTA) have not been reported.

Objectives:
The purpose of this study was to determine the prevalence, characteristics, and treatment strategies of CTO identified by CCTA.

Methods:
We identified 23,745 patients who underwent CCTA for suspected coronary artery disease (CAD) from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry. Baseline clinical data were collected, and allocation to early coronary revascularization performed within 90 days of CCTA was determined. Multivariable logistic regression reporting odds ratios (OR) with 95% confidence intervals (95%CI) was performed.

Results:
Patients with CTO were older (64.7 ± 10.8 vs 57.2 ± 12.6 years, p<0.001) and more often male (74.6% vs 54.1%, p<0.001) compared with patients without CTO. The prevalence of CTO was 1.4% (342/23,745) in all patients and 6.2% in patients with obstructive CAD (≥50% stenosis). The presence of CTO was independently associated with male sex, smoking, hypertension, diabetes, age, and less common atypical angina (Table). Most CTO patients (61%) were treated medically, while 39% underwent coronary revascularization. In patients with severe CAD (≥70% stenosis), CTO independently predicted revascularization by CABG (OR 3.06, 95%CI: 1.88-4.98, p<0.001) but not by PCI (p=0.08).

Conclusions:
CTOs are not uncommon in a contemporary CCTA population and are associated with age, gender, angina status and CAD risk factors. Most individuals with CTO undergoing CCTA are managed medically with higher rates of surgical revascularization in patients with versus without CTO.
Abstract 17579: Quantification of Femoral Adipose Tissue Provides Novel Mechanistic Insights Into the "Obesity Paradox": a Translational Approach
Authors: Antonopoulos Alexios S , Margaritis Marios , Herdman Laura , Coutinho Patricia , Psarros Constantinos , Digby Janet , Krasopoulos George , Petrou Mario , Channon Keith M , Antoniades Charalambos
Published: July 2021

Introduction:
Obesity has been paradoxically associated with a better outcome of CAD patients, while anthropometic measures of obesity provide limited information on adipose tissue (AT) biology. We hypothesised that quantification of femoral AT (FemAT) deposition using U/S can provide mechanistic insights into the obesity paradox.

Methods:
FemAT biopsies from 185 pts undergoing coronary bypass surgery (CABG) were cultured ex vivo for secretome and gene expression studies. FemAT thickness was measured by U/S at both the anterior and exterior surface of the thigh, at the mid point of the distance between the iliac crest and the knee, and the average of both thighs was calculated. Malondialdehyde (MDA), a marker of oxidative stress, was measured in plasma and FemAT culture supernatants. Brachial artery (BA) flow mediated dilatation (FMD) and distensibility were assessed by U/S.

Results:
FemAT thickness was only weakly correlated with BMI (r=0.235, p<0.001) and waist-to-hip ratio (WHR, r=-0.179, p<0.05), suggesting that it provides different information to classic anthropometrics in obesity. Patients with increased FemAT thickness had lower plasma MDA (A), better FMD (B) and greater BA distensibility (C), despite of being more obese. On the contrary BMI did not predict systemic oxidative stress or vascular function, while WHR was weakly correlated only with FMD (rho=-0.156, p<0.05). Increased FemAT thickness was associated with lower MDA release from FemAT culture supernatants (D), and lower IL6-receptor (E) / CD68 (F) expression in FemAT samples, suggesting lower endogenous oxidative stress, and less macrophages’ infiltration.

Conclusions:
Femoral fat accumulation is associated with lower local AT inflammation and favourable systemic effects on vascular function in CAD. Combining imaging with AT biology could help to better understand the role of obesity-related vascular disease and provide an explanation to the “obesity paradox”.
Abstract 17595: The Value of Continuous ST-Segment Monitoring in the Emergency Department: a Quasi-Experimental Pre-Post Study
Authors: Rose Bovino Leonie L , Pelter Michele M , Desai Mayur M , Jefferson Vanessa , Andrews Laura K , Funk Marjorie
Published: July 2021

Purpose:
The AHA Practice Standards for ECG Monitoring recommend continuous ST-segment monitoring (C-STM) in patients presenting to the emergency department (ED) with signs and/or symptoms suggestive of acute coronary syndrome (ACS), but few studies have evaluated its use in the ED. Our aims were to compare the time to diagnosis and 30-day adverse events (return to the ED with signs and/or symptoms of ACS, hospital admission, acute myocardial infarction, use of reperfusion therapy, or mortality) before and after implementation of C-STM. We also evaluated the diagnostic accuracy of C-STM in detecting ischemia or infarction, using stress test and troponin I results as reference standards.

Methods:
We prospectively studied 163 adults (pre-intervention phase: n=78; intervention phase: n=85) in the ED at a single hospital. We stratified patients into low (n=51), intermediate (n=100), or high (n=12) risk using HEART scores. The principal investigator monitored participants, activating C-STM on bedside monitors in the intervention phase. We used likelihood ratios (LRs) as the measure of diagnostic accuracy. By convention, a positive (+) LR is diagnostic at >10 and a negative (-) LR at <0.1.

Results:
Overall, 9% of patients were diagnosed with ACS. There was no significant difference in median time to ACS diagnosis before and after implementation of C-STM (5.55 vs. 5.98 hours; p=0.43 for Mann-Whitney U test). In risk-stratified analyses, no significant pre-post difference in time to ACS diagnosis was found in low-, intermediate-, or high-risk patients. There was no difference in the rate of any 30-day adverse event before vs. after C-STM implementation (11.5% vs. 10.6%; p=0.85 Chi-squared test). None of 3 episodes of ST-segment changes on C-STM represented ACS. The +LR and -LR of C-STM

for ischemia were 24.0 (95% CI 1.4 - 412.0) and 0.3 (95% CI 0.02 - 2.9), respectively; and for infarction were 13.7 (95% CI 1.7 - 112.3) and 0.7 (95% CI 0.3 - 1.5), respectively.

Conclusion:
In this sample of mainly low- to intermediate-risk patients, use of C-STM did not improve time to diagnosis or 30-day adverse outcomes, nor provide much benefit in detecting myocardial ischemia or infarction. Use of C-STM may need to be re-evaluated for patients with low to intermediate risk for ACS in the ED.
Abstract 17638: Systemic Cardiovascular Effects of Intravenous Urocortin 2 and Urocortin 3 in Patients with Heart Failure and Healthy Volunteers
Authors: Stirrat Colin G , Venkatasubramanian Sowmya , Pawade Tania , Mitchell Andrew , Shah Anoop , Hunter Amanda , Lang Ninan N , Newby David E
Published: July 2021

Introduction:
Urocortin 2 (UCN 2) and urocortin 3 (UCN 3) are endogenous peptide hormones with an emerging role in the pathophysiology and treatment of heart failure. For the first time, we examined the systemic cardiovascular effects of both UCN 2 and UCN 3 in healthy volunteers and patients with heart failure.

Methods:
Seven healthy volunteers (Group A) and nine patients with stable chronic heart failure (Group B, New York Heart Association class II and III, left ventricular ejection fraction <35%) on optimal medical therapy underwent non-invasive oscillometric sphygmomanometry and impedance cardiography during incremental intravenous infusions of sodium nitroprusside (0.15/0.5/1.5 μg/kg/min), UCN 2 (0.16/0.48/1.6 μg/min), UCN 3 (5/15/50 μg/min) and saline placebo in a randomised double blind two-way cross over study.

Results:
Other than diastolic blood pressure (78 vs 72 mmHg for Group A and B respectively, p<0.05), haemodynamic variables were similar at baseline of each infusion and were unchanged by saline placebo infusion (p>0.05 for all). SNP, UCN2 and UCN 3 infusions increased heart rate and cardiac index, and reduced systolic and diastolic blood pressure and peripheral vascular resistance index (PVRI) in both healthy volunteers and patients with heart failure (p<0.05 for all; see Figure 1). There were no significant differences in the changes in cardiac index or PVRI between healthy volunteers and patients with heart failure during either UCN 2 or UCN 3 infusions (p>0.05).

Conclusion:
Intravenous UCN 2 and especially UCN 3 increase cardiac output and reduce peripheral vascular resistance. This favourable haemodynamic profile suggests that UCN 2 and UCN 3 hold exciting therapeutic potential for the treatment of acute heart failure.
Abstract 17642: Warfarin versus Dabigatran: The Coagulation Activity in the Left Atrium During Atrial Fibrillation Ablation
Authors: Hashimoto Naoaki , Arimoto Takanori , Yashiro Yoshinori , Iwayama Tadateru , Ishigaki Daisuke , Kumagai Yu , Nishiyama Satoshi , Takahashi Hiroki , Shishido Tetsuro , Miyamoto Takuya , Nitobe Joji , Aoyama Hiroshi , Watanabe Tetsu , Kubota Isao
Published: July 2021

Background:
Atrial fibrillation (AF) ablation is associated with the potential risk of periprocedural thromboembolic events. Previous studies suggested performing AF ablation with continuous warfarin reduced the risk of thromboembolic events, otherwise the safety and efficacy of periprocedural dabigatran was controversial. We aim to compare the differences of the coagulable state in the left atrium (LA) between the anticoagulation strategies.

Methods:
We divided 158 patients who underwent AF ablation into 3 groups: ablation with off warfarin (n=100, WF-off group), ablation with perioperative warfarin therapy (n=33, WF group), and ablation with dabigatran therapy (n=25, D group). Warfarin was stopped 1 day before the procedure in WF-off group. Uninterrupted warfarin therapy was used in WF group and interrupted only on the morning of the procedure with dabigatran in D group. During AF ablation, the blood samples from the LA obtained immediately after the trans-septal puncture before heparin administration in each groups. The D-dimer level and soluble fibrin monomer complex (SFMC) level in the LA were evaluated.

Results:
The prevalence of positive D-dimer (≥ 0.5 μg/ml) in the LA was observed 3% in WF group, 12% in D group, and 23% in WF-off group, respectively. SFMC levels in the LA were significantly lower in WF group compared with WF-off group (p<0.01). SFMC levels in D group tended to be higher compared with WF group, but lower compared with WF-off group.

Conclusions:
The coagulation activity in the LA was lower with perioperative warfarin therapy than with dabigatran therapy. Even transient interruption of anticoagulant therapy may be associated with hypercoagulable status in the LA.
Abstract 17659: The Impact of Routine HbA1c Screening on the Prevalence of Diabetes Mellitus and Outcomes in Patients Undergoing Percutaneous Coronary Intervention
Authors: Abu Tailakh Muhammad , Zahger Doron , Friger Michael , Sidi Aviel , Mazor Efrat , Novack Victor
Published: July 2021

Introduction:
The reported rate of Diabetes Mellitus (DM) in patients undergoing Percutaneous Coronary Intervention (PCI) is 30%-40%. In 2008, the International Expert Committee recommended diabetes diagnosis by HbA1c level ≥6.5%.
Our aim
was to determine the prevalence of previously undiagnosed DM defined by elevated HbA1c in patients undergoing PCI and its association with 1-year clinical outcomes.

Methods:
Consecutive patients undergoing PCI in a large tertiary teaching hospital were enrolled (2011-2013). HbA1c was measured before angiography. The primary outcome was 1-year Major Adverse Cardio- and Cerebrovascular Event (MACCE) defined as death, stroke, PCI or acute MI. Secondary outcomes included short term mortality.

Results:
1313 patients were enrolled (795 with ACS). DM was previously known in 528 (40.2%) patients, 232 (17.7%) had Undiagnosed DM (UDM) based on the HbA1c ≥6.5% and 553 (42.1%) did not have diabetes (Non-DM). In patients with DM HbA1c was 8.0±1.8% as compared 7.6±1.4% in patients UDM (p=0.003). UDM patients were younger (64±11) compared to DM (69±11) and non-DM (64.5±13), p<0.001. In-hospital mortality was 0.9%, 4% and 3.4% in non-DM, DM and UDM patients, respectively (p=0.004). One-year MACCE rates were 18%, 28%, and 19% in non-DM, DM, and UDM groups, respectively (p<0.001). Multivariate analysis showed that compared to non-DM (reference), the DM and UDM groups had MACCE hazard ratios of 2.11 (p<0.001) and 1.06 (p=0.55) adjusted for age, gender, smoking, previous ischemic heart disease and acute coronary syndrome.

Conclusions:
Pre-procedure HbA1c testing leads to the diagnosis of previously unknown DM in a large subgroup of patients undergoing PCI. These patients represent an intermediate group as their short term mortality resembles that of patients with DM while 1-year MACCE rates are similar to non-DM patients, possibly reflecting early detection and treatment. Our findings support routine screening for DM in all patients undergoing PCI.
Abstract 17665: Complementary Role of Von Willebrand Factor Indices to Brain Natriuretic Peptide in Hypertrophic Cardiomyopathy
Authors: Kusumoto Hana , Blackshear Joseph L
Published: July 2021

Introduction:
In hypertrophic cardiomyopathy (HCM), brain natriuretic peptide (BNP) has been weakly associated with septal thickness, diastolic function parameters, resting left ventricular outflow tract gradient ([[Unable to Display Character: ∆]]P), and more strongly associated with prognosis. Von Willebrand factor activity is known to be altered in HCM, and acquired bleeding may occur in up to ¼ of patients.

Hypothesis:
We hypothesized that indices of von Willebrand factor (VWF) activity would be more strongly related to [[Unable to Display Character: ∆]]P than BNP.

Methods:
We compared BNP and three independent measures of VWF function to echo/Doppler parameters in 84 HCM patients.

Results:
In obstructive (resting [[Unable to Display Character: ∆]]P ≥30 mm Hg), n-58 versus labile HCM (resting [[Unable to Display Character: ∆]]P <30 mm Hg, Valsalva [[Unable to Display Character: ∆]]P ≥30 mm Hg), n=28, VWF multimers were abnormal in 90% versus 52% (p=0.0005), VWF activity to antigen ratio was markedly lower, 0.76±0.09 vs 0.89±0.16, p<0.0001, and PFA markedly prolonged, 207±75 versus 129±61 seconds (p<0.0001), while BNP was moderately higher, 331±273 versus176±163 pg/ml, p=0.007. BNP correlated (Spearman rho, ρ), most strongly with echocardiographic E/e’ (ρ=0.51, p<0.001) and left atrial volume (ρ=0.34, p=0.003) but not peak gradient, [[Unable to Display Character: ∆]]P, (ρ=0.13, NS), while BNP normalized for age and gender was weakly associated with [[Unable to Display Character: ∆]]P, ρ=0.26,p=0.02 and powerfully associated with septal thickness (ρ=0.50, p<0.001), and left ventricular mass index (ρ=0.43, p<0.001). In contrast, quantitative VWF activity measures correlated strongly with [[Unable to Display Character: ∆]]P, VWF activity/antigen (ρ=-0.59, p<0.0001), and PFA (ρ=0.51, p<0.0001). In HCM patients with bleeding (n=31), VWF antigen level was higher than in those without bleeding suggesting that the combination of elevated total VWF antigen and absent high molecular weight multimers may be involved in the causation of bleeding.

Conclusion:
Our data suggest that BNP elevations are associated most strongly with E/e’, left atrial volume, septal thickness, and left ventricular mass, while VWF activity indices more strongly reflect [[Unable to Display Character: ∆]]P, and may thus have a complementary role in assessing therapeutic responses and prognosis. Loss of high molecular weight VWF multimers and elevated total VWF antigen concentration may be a novel marker of bleeding risk from acquired von Willebrand syndrome in HCM.
Abstract 17686: Appropriate Use and Clinical Impact of Early Echocardiograms in Hospitalized Patients
Authors: Chiriac Anca , Kadkhodayan Ana , Pislaru Sorin V , Dailey Eric , Buechler Tamara , Newman James , Pellikka Patricia
Published: July 2021

Introduction:
Transthoracic echocardiography (TTE) is a versatile tool for investigating cardiac function in hospitalized patients, but it was recently suggested that only a fraction of the studies result in an active change in management. The importance of early inpatient TTE to guide management and rule out important alternative pathology has not been previously investigated. The opinion of the referring provider has never been systematically surveyed.

Hypothesis:
Appropriate use (AU) of TTE in hospitalized patients has significant implications for patient care, even without resulting in direct alterations in management.

Methods:
We conducted a prospective review of 546 consecutive echocardiograms performed within 72 hours of hospital admission. An electronic survey consisting of 6 questions pertinent to rationale for TTE and consequences to patient care was sent to physicians. AU was independently determined by two investigators blinded to survey results and clinical outcomes, with differences adjudicated by a third independent investigator.

Results:
Of 546 TTEs included in this study, 526 (96%) were appropriate, 2% inappropriate, and 2% uncertain. Although only 48% of responders actively changed management after TTE results, 97% thought the TTE answered their clinical question. At least one new medication change occurred in 190 (35%) patients. Moreover, 95% of physicians would do another TTE in a similar situation, either to guide cardiac therapy, rule out contributing cardiac pathology, or support their current therapeutic plan. Only 5% of responders would not order another TTE if given a similar presentation in the future. Furthermore, our study uncovered a high incidence of unexpected findings (33% of TTEs), ranging from new decrease in LV systolic function, new valvular dysfunction, to pericardial effusion and new aortic aneurysm. These findings have significant clinical implications for the individual patient.

Conclusions:
Most early inpatient TTEs at our institution were appropriate and answered a specific clinical question important for management decisions. Even those not directly altering the acute therapeutic strategy impacted clinical course. A large number of significant incidental findings were recorded.
Abstract 17689: Imaging Mitochondrial Function of Mesenchymal Stem Cells Transplanted to the Myocardium
Authors: Franchi Federico , Peterson Karen M , Paulmurugan Ramasamy , Lerman Amir , Rodriguez-Porcel Martin G
Published: July 2021

Introduction:
Stem cells have poor survival after transplantation, what can limit the use of these therapies. Mitochondrial dysfunction has been recognized as a limiting event that can lead to cell death. Here, we hypothesized that the mitochondrial function of progenitor cells can be monitored
in vivo
using reporter gene-based molecular imaging. A better understanding of the biology of transplanted stem cells in the ischemic myocardium can lead to optimization of cell therapies.

Methods:
Using RT-PCR we identified the antioxidant NAD(P)H:Quinone oxidoreductase (NQO1) enzyme as a marker of mitochondrial dysfunction in mouse Mesenchymal Stem Cells (MSCs) that were treated with a mitochondrial stressor, diethyl maleate (DEM). We then constructed a luciferase reporter gene driven by the NQO1 promoter. After
in vitro
validation, MSCs were transplanted into a mouse model of ischemia/reperfusion (IR, n=4) and mitochondrial function was monitored by bioluminescence imaging.

Results:
MSCs treated with DEM had an increase in NQO1 reporter gene signal that inversely correlated with the amount of the mitochondrial by-product adenosine tri-phosphate (ATP, r = -0.9643, p = 0.0028; Fig 1A). Mitochondrial dysfunction was preserved by the use of a mitochondria-targeted antioxidant Mito-Tempo (MT), correcting ATP and NQO1 luciferase signal.
In vivo
studies showed that MSCs yielded higher Firefly luciferase activity in IR mice compared to sham and this signal was normalized when cells were pre-treated with MT (Fig 1B). Data was confirmed by
ex vivo
measurement of Firefly luciferase activity, which was 4.9-fold higher in the IR group than in shams, after correction for cell number (Fig 1C).

Conclusions:
We have developed a novel imaging strategy that allows noninvasive assessment of the mitochondrial status of transplanted stem cells in the ischemic myocardium. Knowing when transplanted cells “suffer’ from mitochondrial dysfunction may allow optimization of these therapies.
Abstract 17722: Does Aortic Resection without an Open Distal and Hemi-Arch Procedure Address all Regions at Risk of Progression in Bicuspid Aortopathy?
Authors: Barker Alex J , van Ooij Pim , Fedak Paul W , Bonow Robert O , Malaisrie S. Chris , McCarthy Patrick M , Carr James , Collins Jeremy , Markl Michael
Published: July 2021

Introduction:
Aggressive aortic resection strategies for bicuspid aortic valve (BAV) patients with significant aortopathy are sometimes warranted. 4D flow MRI can identify regions of the aorta with elevated wall shear stress (WSS) that may be at risk of disease progression and thus should be resected during aneurysm repair. This study assesses the efficacy of standard aortic resection practices to include areas at risk as determined by preoperative imaging.

Methods:
13 BAV patients (51±17 yrs) undergoing ascending aortic repair received preoperative 4D flow MRI. 10 age-matched normal subjects (50±14 yrs) with healthy tricuspid aortic valves were used to determine the range of physiologically normal WSS. Patient WSS above the healthy 95% confidence interval classified tissue at risk. The surgeon was blinded to the results and postoperative MRI identified the exact region of resection.

Results:
Preoperative mean aortic diameter was 4.7±0.7 cm; the age-matched control diameter was 2.9±0.5 cm (P<0.001). 38% of patients had severe aortic stenosis. All patients had WSS above the physiologic norm. All 5 patients with open distal and hemi-arch repair had complete removal of “at-risk” tissue as defined by elevated WSS. In all 5 cases, resection with the clamp on would have resulted in residual at risk regions. Of the 8 patients with the occluding clamp left on: 4 had regions at risk that matched/were smaller than the resected regions (-9±6% of resection area) while 4 had remaining tissue at risk (36±22% of resection area). The average at risk region remaining was 14±28% of the resection area.

Conclusions:
In selected patients with BAV, aggressive resection using open distal/hemi-arch repair is necessary for complete resection of tissue at risk of disease progression. Less aggressive resections without an open distal anastomosis does not always completely remove “at risk” regions. With further validation, 4D flow MRI could be used to guide patient-specific resection strategies.
Abstract 17739: Time relationship of Cerebral Vascular Accidents and Echocardiographic Diagnosis of Left Ventricular Non-compaction
Authors: Tabaza Luai K , Mickelsen Steven , Khauli Samih
Published: July 2021

Background:
Isolated left ventricular non-compaction (LVNC) in adults is an increasingly recognized cardiomyopathy. It is associated with cerebrovascular accidents (CVA), ventricular arrhythmias (VT), systolic dysfunction, and sudden cardiac death. We set out to better understand the time relationships of CVA and echocardiographic diagnosis in our adult LVNC population.

Methods:
We reviewed unique subject-adult echo reports performed at UIHC between January 2009 and March 2014 (n=20,597; mean follow up after echo was 27 months+/ -16 months); we identified subjects with echocardiographic diagnosis of LVNC. Retrospective chart review was then performed to evaluate clinical variables encompasses an average of 33+/-36 months [up to 23.7years].

Results:
Hypertrabiculation of the LV was observed in 1.67% of all echo studies (n=354); of those 184 individuals met echo criteria for LVNC (0.89%), males represented 63% with mean age of 57+/-16 years. Majority with LVEF<35% (n=105, 57%) averaging 37+/-7% (n=184). Annual mortality was high (7.8%) with 34 subjects (18.4%) dying over the course of follow-up. Approximately one third of patients (n=57, 31%) experienced at least one CVA over the duration of study. First CVA preceded echo diagnosis by an average of 35+/-62 months in the majority of cases (n=20); in a substantial minority CVA was closely associated with echo diagnosis 4.8+/-6 days (n=8). In 4 subjects CVA occurred 17+/-7 months after echo diagnosis. Oral Anticoagulants (OAC) were prescribed in 27% of all subjects and more often in those with CVA events (36%). LVEF was statistically significantly lower in subjects with CVA (p=0.03) and LVEF<35% was more often associated with prescription of OAC (36% vs 17%). In the group with LVEF>35 (61+/-6%) CVA occurred in 12% (n=10) and of those OAC was prescribed in 40% (n=4/10).

Conclusions:
Patients with LVNC have a high incidence of CVA that often precedes echocardiographic diagnosis by years. OAC appear to be underutilized in patients with CVA and LVNC. Low EF appears to be associated with more events, however, CVA was also observed in a substantial number of subjects with relatively preserved LVEF. Future studies are needed to understand the value of primary thromboembolic prevention in this high-risk group.
Abstract 17741: Atrial Fibrillation and Incident End-Stage Renal Disease: the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: O’Neal Wesley T , Tanner Rikki , Efird Jimmy T , Baber Usman , Alonso Alvaro , Howard Virginia , Howard George , Muntner Paul , Soliman Elsayed Z
Published: July 2021

Background:
Recently, it has been shown that atrial fibrillation (AF) is an independent risk factor for end-stage renal disease (ESRD) among persons with chronic kidney disease (CKD). However, the association between AF and incident ESRD has not been examined in the general population.

Methods:
A total of 25,315 study participants (mean age 65 ± 9.0 years; 54% women; 40% blacks) from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. AF was identified in study participants at baseline (2003- 2007) by the study electrocardiogram and self-reported history of a physician diagnosis. Incident cases of ESRD were identified through linkage of REGARDS participants with the United States Renal Data System. Cox proportional-hazards regression was used to generate hazard ratios (HR) and 95% confidence intervals (95%CI) for the association between ESRD and AF.

Results:
A total of 2,190 (8.7%) participants had AF at baseline. Over a median follow-up of 7.7 years, 295 (1.2%) participants developed ESRD. In multivariable adjusted models, AF was associated with an increased risk of incident ESRD (Table 1). However, the association between AF and ESRD became non-significant after adjustment for baseline markers of CKD. Similar results were obtained when albumin-to-creatinine ratio was included in the model as a continuous variable (log-transformed). An interaction between AF and CKD was not detected.

Conclusion:
AF is associated with an increased risk of ESRD in the general population. However, this association potentially is explained by underlying CKD.
Abstract 17752: Altered Expression of Chloride Transporters in Rat Pulmonary Arterial Smooth Muscle Associated with Chronic Hypoxic Pulmonary Hypertension
Authors: Sun Hui , Paudel Omkar , Sham James S
Published: July 2021

Chloride channels play an important role in regulating smooth muscle contraction and proliferation, and contribute to the enhanced vasoconstriction in pulmonary hypertension (PH). The intracellular Cl- concentrations ([Cl-]i) determine the driving force for Cl- conductance, thereby the functional consequence of channel activation. We have previously found that the [Cl-]i was increased in pulmonary artery (PA) smooth muscle cells of rats with chronic hypoxic PH (CHPH), which may lead to an increased depolarizing Cl- efflux during channel activation. Yet how the [Cl-]i is regulated in PA is unknown. Here we examined the expression profile in rat PAs of SLC12 family cation-coupled Cl- cotransporters (CCCs) and SLC4 family of Cl/HCO3 anion exchangers (AEs) that have been shown to regulate the intracellular Cl- homeostasis in other tissues. CHPH was induced by exposing rats to 10% O2 for 3 weeks. Conventional and real-time PCR were used to detect and quantify the mRNA expression in endothelium-denuded intralobal PAs. Normoxic PAs expressed all 9 CCCs and both Na+- dependent (SLC4A8) and -independent AEs (SLC4A1-3). SCL12A2 encoding for Na-K-2Cl cotransporter 1 (NKCC1) showed 45- and 12-fold higher expression than NKCC2-encoding SCL12A1 and Na-Cl cotransporter-encoding SLC12A3, respectively. Among the 4 genes that encode for K-Cl cotransporters (KCC) 1-4, the expression of SLC12A4, 6 and 7 was about 100-1000 fold higher than that of SCL12A5. Control PAs also showed higher SLC4A2 and 3 expression than SLC4A1 and 8. In hypoxic PAs, the expression of SCL12A2 encoding for Cl--accumulating NKCC1 was increased (copy number normalized to that of cyclophilin A served as an internal control: 1.23x10-2±.001, n=6 vs. 6.19x10-3±.0002, n=6, p<0.001) while that of SLC12A7 encoding for Cl--extruding KCC4 was reduced (4.92x10-3±.0005, n=6 vs. 1.14x10-2±.002, n=6, p<0.01), consistent with our previous functional findings. This study provides the first characterization of Cl- transporter expression profile and the first evidence of CHPH-associated transcriptional alterations in Cl- transporters in pulmonary arterial smooth muscle.
Abstract 17773: Peptide Inhibition of PTEN Increases Mouse Survival after Sudden Cardiac Arrest
Authors: Zhu Xiangdong , Wang Huashan , Wang Youhua , Li Jing , Leff Alan R , Vanden Hoek Terry L
Published: July 2021

Introduction:
We recently reported that TAT fusion proteins designed to activate versus inhibit the Akt related phosphatase PTEN in heart cells respectively worsen or significantly improve ischemia/reperfusion injury and contractile functional recovery. We therefore designed a short 20 amino acid peptide PTEN inhibitor, TAT-PTEN9c, for rapid tissue delivery and tissue protection after mouse sudden cardiac arrest (SCA). TAT-PTEN9c contains a TAT protein transduction domain fused to the PTEN C-terminal 9 amino acids of the PDZ-domain binding motif. We hypothesized that TAT-PTEN9c blocks PTEN membrane localization and activation, with corresponding tissue Akt activation and improved SCA survival.

Methods:
Mouse cardiomyocytes were isolated from 1-3 day old mouse pups. Western blot was used to determine the efficacy of TAT-PTEN9c for enhancing Akt phosphorylation in mouse cardiomyocytes exposed to oxidant (H2O2) stress. C57BL6 mice were subjected to an established potassium-induced 8 min SCA protocol. MAP, ETCO2, body temperature and ECG were recorded until 4 h after successful cardiopulmonary resuscitation (CPR). TAT-PTEN9c (7.8 mg/kg) was given intravenously (IV) immediately after CPR (n=10) and a 2nd dose in an additional 5 mice was given at 60 min. IV administration of TAT-GFP was used to measure the kinetics of heart and brain tissue TAT protein delivery.

Results:
The designed TAT-PTEN9c peptide significantly enhanced Akt activation in neonatal mouse cardiomyoctes in a concentration-dependent manner. 30 mice with successful CPR were randomly assigned to receive either saline or TAT-PTEN9c. Survival (versus cardiovascular collapse and death) was significantly increased in TAT-PTEN9c treated group compared with that of saline control at 2 h (14/15, 93% vs. 9/15, 60%, P < 0.05) and at 4 h (10/15, 67% vs. 6/15, 40%, P < 0.05) after CPR. Western blot and immunohistochemistry showed that TAT protein transduction in heart and brain was diffuse and occurred within 5 min after IV administration.

Conclusion:
TAT-PTEN9c can be used after CPR in a mouse SCA model to rapidly enhance Akt activation in critical organs and prevent early cardiovascular collapse and death.
Abstract 17788: Association of Left Atrial Function and Left Atrial Fibrosis in Patients with Atrial Fibrillation: a Cardiac Magnetic Resonance Study
Authors: Habibi Mohammadali , Lima Joao , Khurram Irfan , Zimmerman Stefan L , Zipunnikov Vadim , Fukumoto Kotaro , Spragg David , Ashikaga Hiroshi , Rickard John , Marine Joseph E , Calkins Hugh , Nazarian Saman
Published: July 2021

Introduction:
Atrial fibrillation (AF) is associated with left atrial (LA) electrical, structural, and contractile remodeling. Cardiac magnetic resonance (CMR), late gadolinium enhancement (LGE) and feature tracking are capable of noninvasive quantification of LA fibrosis and myocardial motion, respectively.

Hypothesis:
Increased LA fibrosis measured with LGE is associated with worsening of the phasic LA function measured with feature tracking CMR.

Methods:
The cohort included 90 patients (age 61 ± 10 years, 76% male) with symptomatic drug-resistant AF referred for ablation. Peak global longitudinal LA strain (PLAS), LA systolic strain rate (SR-s), and early (SR-ed) and late diastolic (SR-ld) strain rates were measured using cine-CMR images acquired during sinus rhythm. The degree of LGE was quantified using normalized image intensity.

Results:
Compared to patients with paroxysmal AF (60% of cohort), those with persistent AF had larger maximum LA volume index (LAVImax, 56 ± 17ml/m2 versus 49 ± 13ml/m2 p=0.036), and increased LGE (27.1± 11.7% versus 36.8 ± 14.8% p<0.001). Aside from LA active emptying fraction, all LA parameters (passive emptying fraction, PLAS, SR-s, SR-ed and SR-ld) were lower in patients with persistent AF (p< 0.05 for all). Increased LA fibrosis was associated with lower LA passive emptying fraction, PLAS, SR-s, SR-ed, and SR-ld after adjusting for age, sex, hypertension, heart failure, left ventricular ejection fraction, type of AF, and LA volume (p<0.05 for all).

Conclusions:
Increased LA fibrosis is associated with decreased LA reservoir, conduit, and booster pump functions. Phasic measurement of LA function using feature-tracking CMR is feasible and may add important information regarding the physiological importance of LA fibrosis.
Abstract 17827: Klf5 Mediates Glucose-driven Changes ofCcardiac Pparα in Diabetes
Authors: Drosatos Konstantinos , Pollak Nina M , Willecke Florian , Ntziachristos Panagiotis , Trent Chad M , Hu Yunying , Schulze P. Christian , Aifantis Iannis , Goldberg Ira J
Published: July 2021

Krüppel-like factors (KLF) affect metabolism. Lipopolysaccharide-induced sepsis reduced cardiac PPARα and increased KLF5 (8-fold) more than any cardiac KLF isoform detected by whole genome microarray analysis. In silico analysis of ppara gene promoter predicted two KLF5 binding sites that overlap with c-Jun (AP-1) binding sites: -792/-772 bp and -719/-698 bp. Infection of a mouse cardiomyocyte cell line (HL-1) with adenovirus expressing constitutively active c-Jun reduced, while Ad-KLF5 increased PPARα mRNA in a dose-dependent manner. Chromatin immunoprecipitation (ChIP) showed that c-Jun binds both -792/-772 bp and -719/-698 on ppara promoter while KLF5 binds on -792/-772 bp. ChIP on LPS-treated HL-1 cells showed that c-Jun binding on -792/-772 bp prohibits KLF5 binding. We generated a cardiomyocyte-specific KLF5 knockout mouse (αMHC-KLF5-/-), which had 50% normal cardiac function. Cardiomyocyte-specific KLF5 ablation reduced PPARα (50%) and several fatty acid metabolism-associated genes such as CD36 (40%), LpL (20%), PGC1α (45%), AOX (28%) and Cpt1 (45%). As PPARα regulates cardiac fatty acid metabolism, we tested whether cardiac KLF5 is modulated in diabetes, when cardiac PPARα and lipid changes occur. I.p. injection of streptozotocin (STZ) in C57BL/6 mice increased plasma glucose (2.9-fold) and reduced cardiac KLF5 and PPARα gene expression; similar to STZ-treated rats but unlike what had been found in a different mouse strain (C57BL/6 x DBA2) treated with STZ. Treatment of HL-1 cells with increased glucose-containing medium (1 mg/ml) reduced KLF5 (80%) and PPARα (65%), as well as fatty acid metabolism markers, such as AOX (85%), Cpt1β (70%), LCAD (80%) and VLCAD (85%). On the other hand GLUT1 and GLUT4 were increased (30% and 20%) and PDK4 was reduced (65%) indicating increased glucose utilization. A model of non-insulin dependent hyperglycemia (ob/ob mice) had reduced cardiac KLF5 (60%) and PPARα (65%). Correction of hyperglycemia in STZ-treated C57BL/6 mice by pharmacological (dapagliflozin) or antisense oligonucleotide inhibition of kidney’s sodium glucose transporter 2 (SGLT2), restored KLF5 and PPARα gene expression. Thus, KLF5 is a transcriptional regulator of cardiac PPARα that is driven by changes in plasma glucose levels
Abstract 17843: Visceral Adipose Tissue Secretion of Adiponectin Decreases with Increased Body Mass Index
Authors: Rengel Lenore R , Obi Brittaney , Gould Jon , Goldblatt Matthew , Kastenmeier Andrew , Wallace James , Frelich Matthew , Nicholson Kay , Sahoo Daisy , Kidambi Srividya
Published: July 2021

Introduction:
Peripheral adiposity is associated with better metabolic health and higher plasma adiponectin (ADPN) levels. Since ADPN is secreted mainly by adipose tissue (AT), it is intriguing that higher visceral adipose tissue (VAT) is associated with lower ADPN levels and poor metabolic health.

Hypothesis:
We hypothesized that various AT depots differ in their ability to secrete ADPN.

Methods:
Paired AT samples (VAT and subcutaneous adipose tissue (SAT)) were collected from 19 subjects (10 women, 15 obese) undergoing elective abdominal surgery. The samples were cultured and the supernatant was collected after 24 hours. ADPN levels released into the supernatant from VAT and SAT were measured using multiplex methods. Subjects were defined as obese or non-obese (NO) based on BMI > or ≤ 30kg/m2 respectively. Obese subjects were further classified as metabolically unhealthy obese (MUO) or metabolically healthy obese (MHO) based on presence or absence of type 2 diabetes mellitus, hypertension, or cardiovascular disease at the time of surgery.

Results:
Mean ADPN secretion levels from SAT and VAT were similar in NO subjects (17.3 ± 3.4 vs. 9.8 ± 13.0 ng/mL/mg, p=0.5) whereas the mean ADPN secretion was lower from VAT among obese subjects (15.9 ± 0.8 vs. 4.5 ± 0.2 ng/mL/mg, p=0.0002). ADPN secretion decreased from VAT (r=-0.16) and increased from SAT (r=0.33) with increased BMI (Fig.1). When MHO and MUO were compared, ADPN secretion from VAT in MHO was reduced only slightly (16.1 ± 8.2 vs. 4.0 ± 2.0 ng/mL/mg, p=0.07) whereas ADPN secretion was significantly reduced in MUO (15.9 ± 5.3 vs. 4.7 ± 4.6 ng/mL/mg, p=0.003).

Conclusions:
Reduced ADPN secretion from VAT in subjects with increasing BMI may explain lower circulating ADPN levels in obese individuals. Higher ADPN production from SAT and the relatively preserved secretion of ADPN from VAT may explain metabolic health in some obese individuals. Futures studies will help identify factors that control ADPN secretion from AT.