bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18413: Systolic Circumferential Strain Derived From Feature-Tracking Cardiovascular Magnetic Resonance Predicts Survival After Cardiac Resynchronization Therapy
Authors: Taylor Robin J , umar Fraz , Lin Lai S , Ahmed Amar , Steeds Rick P , Leyva Francisco
Published: April 2024

Objective:
The clinical outcome of cardiac resynchronization therapy (CRT) is variable. Feature-tracking cardiovascular magnetic resonance (FT-CMR) allows quantification of myocardial strain using a routine CMR scan. We hypothesized that pre-implant peak systolic circumferential strain (Ecc) predicts survival after CRT.

Methods:
In this prospective study, 98 patients (age: 66 ± 12 yrs, LVEF: 24 ±11%, QRS: 145 ± 30ms) had pre-implant assessment of peak systolic Ecc from the mid cavity LV short-axis slice. This measure, which involved 1.2 ± 0.3 min of post-processing, was assessed in relation to all cause mortality.

Results:
The mean peak systolic Ecc was 7.5 ± 5.0% amongst the entire cohort. 30 patients died over a follow-up of 3.9 ± 2.4 yrs (mean ± SD). Above an optimum cut-off of 10%, Ecc, predicted survival after CRT (Chi-squared: 5.37, log-rank p = 0.01; area under the receiver-operator characteristic curve: 0.67, 95% CI 0.58 - 0.79, p = 0.003).

Conclusion:
The rapid assessment of pre-implant peak systolic Ecc derived from FT-CMR predicts survival after CRT.
Abstract 18459: MicroRNA-712 Induced by Angiotensin II Plays a Key Role in Development of Abdominal Aortic Aneurysm in Mouse
Authors: Kim Chanwoo , Kumar Sandeep , Son Dong Ju , Jang In-Hwan , Jo Hanjoong
Published: April 2024

Abdominal aortic aneurysm (AAA) is a complex vascular disease and a major cause of mortality. AAA is characterized by a weakening of the vessel wall, followed by progressive expansion of the diseased aortic segment. Although the molecular mechanisms underlying AAA initiation and development are poorly understood, microRNAs (miRNAs) are thought to play a role in these processes. Here we identify microRNA-712 (miR-712) through a microRNA array study as a novel miRNA upregulated in abdominal aortic endothelium in mice infused with angiotensin II (AngII, 1 ug/kg/min for 12 to 36 hours). Through
in silico
analysis and using gain-of-function [pre-miR-712] and loss-of-function [locked nucleic acid (LNA)-based anti-miR-712] studies, we determined that miR-712 directly regulates the expression of tissue inhibitor of metalloproteinase 3 (TIMP3). Additionally, we confirmed the target-binding activity of miR-712 on the 3’UTR of TIMP3 by dual-luciferase reporter assay. Furthermore, inhibition of miR-712 decreased matrix metalloproteinase (MMP) activity in an AngII-infused abdominal aorta wall. Finally, we showed that inhibition of AngII-induced miR-712 by subcutaneous injection of anti-miR-712 reduced AAA incidence from 80% (8/10) to 20% (2/10) and maximal aortic diameter from 2.1±0.6mm to 1.2±0.4 mm compared to mismatched control in ApoE
-/-
mice via MMP-mediated mechanisms. Our findings show that miR-712 regulates MMPs activity through the endogenous regulator TIMP3, which leads us to conclude that AngII-induced miRNAs such as miR-712 play important roles in the pathogenesis of AAA. These results suggest that manipulation of miR-712, and its target gene TIMP3 may hold promise as a therapeutic strategy to prevent the development of AAA.
Abstract 18461: Myocardial Infarction With Normal Coronary Angiography and Computed Tomography Angiography
Authors: Panayi Georgios , Wieringa Wouter G , Pundziute Gabija , Alfredsson Joakim , Engvall Jan , Persson Anders , Swahn Eva
Published: April 2024

Background:
Three to five percent of patients, who fulfil the criteria for AMI, have angiographically normal coronary arteries. The mechanisms that cause AMI in the patient with no visible coronary atherosclerosis on the invasive coronary angiography (ICA) are still debatable. The aim of this study was to assess the presence and characteristics of atherosclerotic plaques on computed tomography coronary angiography (CTCA) in patients with AMI who have no visible coronary plaques on ICA.

Methods and Results:
Patients with AMI without visible coronary plaques on ICA underwent CTCA within three days after ICA. 30 patients were enrolled in the study. According to local routine, echocardiography was performed in the majority (26/30) of patients. Twenty-eight patients presented with NSTEMI and two with STEMI. Mean age of the study population was 60.2 years and 23/30 were women. A total number of 452 coronary segments were analysed. A total of 24/30 (80%) patients had normal coronary arteries and 6 patients had coronary atherosclerosis on CTCA. In case of atherosclerosis, the median number of segments with plaque per patient was one. 12/26 patients had completely normal echocardiography results, 11/26 patients had only wall motion abnormalities (WMA), 2/26 patients had WMA with minimal pericardial effusion and 1 patient had only minimal pericardial effusion.

Conclusions:
Despite a diagnosis of AMI, the majority of patients (80%) with a completely normal ICA showed no coronary plaques on CTCA. The remaining 20% of patients had only minimal non-obstructive atherosclerosis. The previously proposed mechanism of AMI due to rupture of a non-obstructive-, invisible on ICA-, plaque could only account for a minority (20%) of this study population. Our data suggest that most patients either had AMI caused by a mechanism not involving plaque rupture or did not have an infarction at all. Having in mind what consequences a diagnosis of AMI confers to the patient it is reasonable to extend the diagnostic evaluation of these patients to cardiac MRI for excluding myocarditis and/or intravascular imaging (optical coherence tomography or intravascular ultrasound) to provide information about some mechanisms of coronary damage (i.e. dissection).
Abstract 18473: Oxidative Stress Improves Coronary Endothelial Function Through Activation of the Pro-Survival Kinase AMPK
Authors: Shafique Ehtesham , Choy Wing , Liu yuhong , Feng Jun , Bianchi Cesario , Benjamin Laura E , Sellke Frank W , Abid Ruhul
Published: April 2024

Introduction:
Failure of several multi-center clinical trials using antioxidants to improve outcomes in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived reactive oxygen species (ROS) in endothelial function challenge a long-held notion that higher ROS levels are harmful for vascular function.

Hypothesis:
We examined the hypothesis that endothelium-specific conditional increase in NADPH oxidase-derived ROS will induce stress-signal-mediated activation of eNOS and thus improve coronary endothelial function.

Methods:
We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8±0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined the effects of increased ROS on EC signaling and coronary endothelial function using eight animals in each group (Tet-ON and Tet-OFF).

Results:
First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart (MHEC), we demonstrate that Nox2-derived ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. We also show that endothelium-dependent coronary vasodilation in Tet-OFF Nox2 animals was CaMKKβ-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death in these animals. Together, these results suggest that activation of AMPK plays an important role in EC survival and endothelial function during oxidative stress.

Conclusion:
These findings suggest that increased ROS levels, often associated with pathophysiological conditions, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
Abstract 18482: Structure Based Prediction of Stability and Affinity Changes in Human NKX2.5 HD Mutants
Authors: Pradhan Lagnajeet , Kasahara Hideko , Nam Hyun Joo
Published: April 2024

Background:
Cardiac transcription factor, NKX2.5, binds to the target DNA through its homeodomain (HD). To date, nearly 40 mutations in NKX2.5 have been found related to familial congenital heart disease. Homeodomain missense mutations have a high disease penetrance, with pleiotropic cardiac defects compared to missense mutations outside the homeodomain. In in vitro studies, the best correlation with clinical phenotypes and homeodomain mutation resulted from the markedly reduced DNA binding. We recently determined crystal structure of NKX2.5 HD bound to its natural DNA target. Using the structure, we sought to study whether DNA binding and folding energy changes in mutant proteins can be predicted through computational approaches.

Methods and results:
We used structure based energy prediction to calculate the binding energy and the stability of NKX2.5 mutant proteins. NKX2.5 HD from the high resolution crystal structure (PDB ID:
3RKQ
) was mutated to reflect the 14 genetic and 4 somatic point mutations identified in patients with cardiac anomalies. The HD-DNA models were energy minimized using the program Interface Model. This program utilizes a conservative approach by keeping the backbone structure of the protein and DNA intact while operating only on the sidechain rotamers to achieve the lowest energy state using monte-carlo simulation. Intra-protein and protein-DNA interaction energies of mutant models were calculated and the relative ΔG from the wild type was tabulated. Compared to the wild-type, all the genetic mutants showed reduced DNA binding while the somatic mutations show increased protein stability and DNA binding. The prediction is in good agreement with reported biochemical studies.

Conclusion:
The high resolution structure enables prediction of energy changes in NKX2.5 pathological mutants compared to wild type. The results well correlate with previously reported experimental data.
Abstract 18483: Randomized, Double Blind Trial of Tapered versus Abrupt Interruption of Long Term Clopidogrel Therapy After Drug-Eluting Stent Implantation - ISAR-CAUTION
Authors: Fiedler Kathrin A , Mehilli Julinda , Kufner Sebastian , Rifatov Nonlag , Schlichting Anna , Holle Heidrun , Ibrahim Tareq , Laugwitz Karl-Ludwig , Kastrati Adnan , Schulz Stefanie
Published: April 2024

Purpose:
Observational data suggest clustering of thrombotic events after cessation of antithrombotic therapy in patients with coronary artery disease. The underlying mechanism has been ascribed to a potential rebound platelet activity after discontinuation of chronic clopidogrel therapy. This may have a negative impact particularly in patients receiving drug-eluting stents. We therefore hypothesized that gradual clopidogrel therapy cessation attenuates the potential risks associated with abrupt clopidogrel therapy cessation in that patient population.

Methods:
Patients with planned discontinuation of chronic clopidogrel therapy after drug-eluting stent implantation were randomized in a double-blinded fashion to either gradual or abrupt interruption of clopidogrel therapy. The primary endpoint is a composite of cardiac death, myocardial infarction, stroke, stent thrombosis (definite or probable), major bleeding or rehospitalisation due to an acute coronary syndrome at 3 months after randomization. The trial is registered with ClinicalTrials.gov Identifier:
NCT00640679
.

Results:
Enrollment was stopped prematurely due to slow recruitment. A total of 782 patients were enrolled. Follow-up has been completed. Results will be available in June 2013.

Conclusions:
The results will help to define the best way of clopidogrel therapy cessation after drug-eluting stent implantation.
Abstract 18500: Determinants of Cardiac Loading During Long Duration Spaceflight
Authors: Shibata Shigeki , Hastings Jeffrey L , Abdullah Shuaib M , Bungo Michael W , Platts Steven , Hamilton Douglas R , Levine Benjamin D
Published: April 2024

INTRODUCTION:
Prolonged exposure to microgravity (bedrest) leads to a decrease in cardiac mass by ~1%/week due to reduced cardiac work. However, the magnitude of reduction with long duration spaceflight with modern countermeasures is unknown. One purpose of this study (Integrated CardioVascular) is to quantify cardiac work and mass in astronauts during 6 months on the International Space Station (ISS).

METHODS:
Data from 5 astronauts who completed a long duration stay on the ISS (~6 months) were analyzed. Cardiac mass (MRI) was measured pre- and post-flight. Continuous finger blood pressure waveforms (Volume-Clamp) for 24 hours were measured before and the end of flight (15 days before they returned to the earth). Cardiac mass was estimated by (epicardial volume - endocardial volume)*1.05 g/mL. Daily stroke work and cardiac work were calculated by the sum of each stroke volume (ΣSV, SV; stroke voluem) and stroke work (ΣSV*cmBPs, cmBPs; mean central blood pressure during systole) per day, respectively. The central blood pressure waveform was mathematically reconstructed from the finger blood pressure waveform. Beat-to-beat SV was estimated with BP waveform analysis (Modelflow).

RESULTS:
The %change in cardiac mass was variable (+1% on average) with divergent responses among astronauts (-4%~ +14%). All astronauts showed the reduction of cardiac work (-15±9%), while 4 of 5 showed the reduction of stroke work (-8±12%). A strong positive linear relationship was shown between % changes in cardiac work vs. mass (R
2
=0.471) as well as %changes in stroke work vs. cardiac mass (R
2
=0.905).

CONCLUSIONS:
Cardiac atrophy during long duration spaceflight is highly dependent on the relative changes in cardiac work and stroke work from preflight to the end of the mission. Current countermeasures may be protective in some, but not all astronauts.
Abstract 18503: Barriers to Linkage to Hypertension Care in Rural Western Kenya: A Qualitative Analysis
Authors: Vedanthan Rajesh , Naanyu Violet , Kamano Jemima H , Rotich Jackson , Lagat Kennedy K , Kiptoo Peninah , Hutchinson Claire , Menya Diana , Kimaiyo Slyvester , Fuster Valentin , Horowitz Carol R , Inui Thomas S
Published: April 2024

Introduction:
Hypertension is the leading global risk factor for mortality and its prevalence is rising in sub-Saharan Africa (SSA). Unless adequately controlled, hypertension will impose large health and economic burdens. Since delays in seeking hypertension care are associated with increased mortality, a critical component of hypertension control is to facilitate early and sustained access of affected individuals to clinical services. However, specific barriers to linkage to hypertension care in SSA are not known.

Objective:
To evaluate barriers to linkage to hypertension care in rural western Kenya, using a qualitative research approach.

Methods:
Six mabaraza, or community gatherings (123 men, 119 women), and 17 focus group discussions (88 men, 81 women) were conducted among community health workers, community members, and hypertensive patients, across a spectrum of age, sex, occupation, and distance from health facility. Content analysis was performed with NVivo 10, identifying key themes representing distinct barriers, which were then classified into a modified Health Belief Model. Ranking of identified barriers was performed using triangulation of participant response density, Delphi method of investigator assessments, and published literature.

Results:
The salient barriers and corresponding proposed solutions are summarized in the Table. Cognitive issues related to knowledge of hypertension and its risks and management were commonly reported by participants. Emotional elements, particularly HIV stigma and fear, were highlighted. Environmental barriers such as finances, distance, and quality of service also featured prominently.

Conclusion:
Linkage to hypertension care is a critical component to a successful hypertension care delivery program. However, successful execution is contingent upon addressing potential barriers at the cognitive, emotional, and environmental levels.
Abstract 18512: Left Ventricular Diameter Adds Prognostic Value to Ejection Fraction in Risk Stratification for Sudden Cardiac Death
Authors: Narayanan Kumar , Reinier Kyndaron , Teodorescu Carmen , Uy-Evanado Audrey , Chugh Harpriya , Nichols Gregory A , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: April 2024

Introduction:
Current approaches to risk stratification for sudden cardiac death (SCD) rely almost exclusively on the left ventricular (LV) ejection fraction (EF). LV size is routinely measured in the echocardiogram but has not been considered in risk assessment.

Hypothesis:
We assessed the hypothesis that consideration of LV diameter improves SCD risk assessment in those with low EF.

Methods:
From a large ongoing, population-based study of SCD in a metro region of the Northwestern US (population approximately 1 million), SCD cases age ≥ 18 years with echocardiograms available prior (but unrelated) to the SCD event were compared with population-based controls. Severe LV dysfunction (LVD) was defined as EF ≤ 35%. LV size, measured using the LV internal dimension in diastole (LVIDD), was categorized as normal, mild, moderate or severe dilatation using American Society of Echocardiography (ASE) recommended cut-offs. Case-control comparisons were performed using the t-test or chi-square test and multiple logistic regression.

Results:
Case subjects (n=418) were slightly older than controls (n=329) (69.5 ± 13.8 vs. 67.7 ± 11.9; p=0.06), were more likely to be African American (11.8% vs 4.2%; p < 0.001), and more commonly had severe LVD (30.5 % vs. 18.8%; p=0.001). The mean LV size (52.2 ± 10.5 mm vs. 49.7 ± 7.9 mm; p < 0.001 ) and LV size index adjusted for body surface area (BSA) (26.6 ± 5.3 mm/m
2
vs. 25.4 ± 4.2 mm/m
2
; p = 0.001) were significantly higher in cases. Moderate or severe LV dilatation (16.3% vs. 8.2%; p = 0.001) and severe LV dilatation (8.1% vs. 2.1%; p < 0.001) were significantly more likely to be observed in cases. In multivariable logistic regression, severe LV dilatation was an independent predictor of SCD (OR 2.5; 95% CI 1.03-5.9; p=0.04), adjusting for age, black race and low EF. Subjects with both low EF and severe LV dilatation had an OR for SCD of 3.8 (1.5-10.2) while for those with only low EF, the OR was 1.7 (1.2-2.5) suggesting that severe LV dilatation additively increased the risk of SCD.

Conclusions:
Increased LV diameter adds incremental prognostic value to LVEF in risk prediction for SCD in the community; this readily available echocardiographic measure warrants further evaluation.
Abstract 18514: Rottlerin Greatly Improves Cardiac Functional Recovery Following Ischemic Cardioplegic Arrest (CP) in Wild-Type but Not BKCa Channel Knockout Mice
Authors: Cordeiro Brenda , Sellke Frank W , Clements Richard T
Published: April 2024

Introduction:
Mitochondrial BKCa channels are thought to provide protection during ischemic insults in the heart. Rottlerin, has been implicated as a potent BKCa activator, however this has not been firmly established. The purpose of this study was twofold: 1) investigate the efficacy of BKCa channel activation as a cardioprotective agent during cardioplegia/reperfusion (CP/R) and 2) assess the specificity of rottlerin for BKCa channels.

Methods:
Wt and BKCa KO mice were subjected to an isolated heart model of CP/R. Hearts were perfused for 30 min at 37C (baseline), followed by intermittent cold hypoxic CP with or without rottlerin (St Thomas II, 10C), and normoxic 37C reperfusion for 30 min. Mechanism of rottlerin-induced cardioprotection was also investigated using H9c2 cells subjected to in vitro CP/reoxygenation and assessed for mitochondrial membrane potential (TMRE) and ROS (DCFDA) production.

Results:
CP/R decreased LVDP (61.6 +/- 6 % baseline, n=6 ), +/- dP/dt (76.6+/- 7.3, 63.4 +/-7.7, % baseline respectively) and coronary flow (CF) (69.6+/-6.0 % baseline) in wt mice. Rottlerin, (100 nM (n=3), 500 nM (n=6)) dose dependently increased the recovery of LV function and CF to near baseline levels (% baseline 500 nM rottlerin, LVDP: 87.6+/- 4.0, +/-dPdt: 97.6 +/- 5.9, 90.9+/- 6.6, and CF: 125.3 +/-22.8, all p<.01 vs CP ). BKCa KO hearts treated with (n=7) or without (n=7) 500nM rottlerin, were similar to wt CP hearts (% baseline BKCa KO + 500 nM rott: LVDP: 66.9+/- 6.0, +/-dP/dt 73.0 +/-3.6, 65.2+/- 4.2, and CF: 94.1 +/- 9.0). H9c2 cells subjected to in vitro CP/R, displayed reduced mitochondrial membrane potential (39 +/-.09 % decrease) and increased ROS generation (50+/-.04% increase), both of which were significantly (p<.01) normalized by rottlerin (100 nM-1 uM) (n=8).

Conclusions:
Activation of BKCa channels profoundly rescues ischemic damage associated with CP/R, likely via effects on improved mitochondrial membrane potential and reduced ROS generation.
Abstract 18524: Left Atrial Function is Associated With Cardiopulmonary Performance in Heart Failure With Preserved Ejection Fraction: A Relax Substudy
Authors: Shah Ravi V , Abbasi Siddique A , McNulty Steven , Hernandez Adrian , Neilan Tomas G , Haines Phillip G , Semigran Mark , Borlaug Barry A , Lewis Gregory , Jerosch-Herold Michael , Kim Raymond J , Redfield Margaret , Kwong Raymond Y
Published: April 2024

Introduction:
Impaired left atrial (LA) function may limit optimal cardiac performance, reflecting both LA load and atrial dysfunction in HFpEF. The link between MRI-derived LA characteristics and exercise capacity in HFpEF has not been studied.

Hypothesis:
We hypothesized that total LA emptying fraction (LAEF) is reduced in HFpEF vs. healthy controls and LA functional impairment would be correlated with LV diastolic dysfunction, vascular dysfunction, and exercise intolerance. As LA hypertension may increase right ventricular load and limit increases in pulmonary perfusion with exercise, the correlation of LAEF with ventilatory efficiency (VE/VCO2 slope) was also examined.

Methods:
Baseline exercise, echo, and cardiac MRI data from RELAX (a study of sildenafil in HFpEF) in patients in sinus rhythm with a measureable LAEF by MRI (n=100) were utilized. Healthy volunteers (n=21) were included for comparison. LAV was measured by the biplane area-length method using 2-/4-chamber SSFP CMR. LAEF was defined as total (ΔLAVmax-min), passive/conduit (ΔLAVmax-before atrial contraction ), and active (ΔLAVbefore atrial contraction-min), each divided by maximal LAV.

Results:
As compared to controls, LAEF (particularly passive conduit function) was reduced in HFpEF (Table 1). In HFpEF, patients with lower LAEF had a larger LA, more echo diastolic dysfunction, higher PA systolic pressure and NT-proBNP, reduced aortic distensibility, worse exercise capacity, and ventilatory inefficiency (Table 2).

Conclusions:
LA function is impaired in HFpEF, may serve as a marker of chronic LA hypertension and may contribute to impaired exercise intolerance and ventilatory inefficiency.
Abstract 18531: Adrenergic Stimulation Enhances Mitochondrial Ca
2
+ Uptake and Cell Death Signaling Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca
2
+ Uniporter
Authors: O-Uchi Jin , Jhun Bong Sook , Hurst Stephen , Raffaello Anna , Ainbinder Alina , Dirksen Robert T , Sun Jianxin , Rizzuto Rosario , Sheu Shey-Shing
Published: April 2024

Introduction:
Mitochondrial Ca
2+
homeostasis is crucial for balancing cell survival and death. The recent breakthrough discovery of the molecular identity of the mitochondrial Ca
2+
uniporter pore (MCU) opens new possibilities for applying genetic approaches to study the role of mitochondrial Ca
2+
regulation in cardiac cells. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca
2+
entry through post-translational modifications of MCU are completely unknown.

Hypothesis:
Persistent adrenergic signaling induces mitochondrial Ca
2+
overload and activates cell death signaling through MCU tyrosine phosphorylation.

Methods:
Tyrosine kinase activation and tyrosine phosphorylation of MCU were observed in rat neonatal cardiomyocytes and H9C2 cardiac myoblasts. Mitochondrial Ca
2+
and reactive oxygen species (ROS) were measured using mitochondrial matrix-targeted Ca
2+
-sensitive inverse pericam and MitoSOX, respectively. Mitochondrial permeability transition pore (mPTP) activity was observed by monitoring the release of GFP-tagged mitochondrial protein, Smac-GFP, using confocal microscopy.

Results:
α
1
-adrenoceptor (α
1
-AR) signaling activates mitochondria-localized Ca
2+
-dependent tyrosine kinase named proline-rich tyrosine kinase 2 (Pyk2) and accelerates mitochondrial Ca
2+
uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, persistent α
1
-AR stimulation increases ROS production, mPTP activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca
2+
overload. Moreover, pretreatment of a potent Pyk2 inhibitor PF-431396 or overexpression of dominant-negative mutant of MCU effectively inhibited α
1
-AR-mediated ROS generation and mPTP activation.

Conclusion:
The α
1
-AR-Pyk2 dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca
2+
entry and apoptosis in cardiac cells. Pyk2-MCU signaling may become novel potent therapeutic targets for preventing mitochondrial Ca
2+
overload, oxidative stress and cardiac injury under pathophysiological states such as heart failure, where catecholamine levels highly increase.
Abstract 18552: Six Months of a Low-Carbohydrate versus Low-Fat Weight Loss Diet Plus Exercise: Effects on Resting and Postprandial Endothelial Function
Authors: Stewart Kerry J , Dobrosielski Devon A , Silber Harry A , Shapiro Edward P , Wang Nae-Yuh , Ouyang Pamela
Published: April 2024

Background:
A worry about low-carbohydrate (CHO) diets is that higher fat meals may adversely affect vascular function acutely, and the regular eating of such meals may lead to chronic vascular impairment. We hypothesized that the effects of a low-CHO vs. low-fat weight loss diet, each combined with exercise training for 6-months, would have similar effects on resting and postprandial endothelial function.

Methods:
Persons (n=77), BMI 25-42 kg/m2, 30-65 years, were randomly assigned to a low-CHO or low-fat diet, plus exercise. At 0 and 6 months, reactive hyperemia was induced after 5 minutes of upper arm occlusion of SBP. The reactive hyperemia peripheral arterial tonometry index (RH-PAT), a measure of endothelial function, was obtained at rest and 4 hours after eating a McDonald’s breakfast (900 calories, 50 fat grams). We also measured body weight, BMI, and total body fat and trunk fat % by dual-energy X-ray absorptiometry.

Results:
Sixty subjects (low-CHO group: n=31, 74% female; low-fat group, n=29, 72% female) completed the study. At 0 months, there were no group differences in the following and the combined values are: age, 50.0±8.7 years; weight, 215.4±32.7 lbs; BMI, 34.2±3.8 kg/m2; total body fat, 43.3±7.2%; trunk fat, 46.4±5.7%; RH-PAT, 2.32±0.44%. At 0 months, RH-PAT did not change in response to the meal in either group, overall -0.05±0.64, p=.58. At 6 months, low-CHO vs. low-fat subjects had a greater reduction in weight, -28.9±11.0 vs. -18.7± 2.0 lbs., p<.01; BMI, -4.7±2.0 vs. -2.9±1.7, p<.01; body fat, -6.8±4.5 vs. -4.0±3.9%, p<.02. The groups did not differ in loss of trunk fat, with an overall drop of - 5.5±5.7%, p<.01. At 6 months, there was no change in resting RH-PAT in either group vs. 0 months, overall +0.03±0.53, p=.64 and no group difference in resting vs. postprandial RH-PAT, overall -0.08±0.69, p=.34. Though the 6-month mean resting RH-PAT did not improve, each absolute 1% drop in trunk fat % was associated with an absolute 0.29% (relative 12.5%) increase in RH-PAT, p=.05. Body composition changes did influence postprandial RH-PAT.

Conclusions:
We found no adverse effects of 6-months of a low-CHO diet on resting or postprandial endothelial function. Central fat loss was associated with improved vascular function, regardless of diet.
Abstract 18558: Exploring Site Level Variation in Radiation Exposure in the VA: Insights From CART
Authors: Carey Evan P , Tsai Thomas T , Baron Anna , Grunwald Gary , Klein Andrew , Vidovich Mladen , Zimmet Jeffrey , Bradley Steven M , Maddox Thomas M , Rumsfeld John S , Ho P M
Published: April 2024

Background:
Prior studies have assessed variation in radiation use and fluoroscopy times for patients undergoing coronary angiography (CA) and percutaneous coronary intervention (PCI); however, the extent that this varies by cath labs is unknown.

Methods:
We analyzed data from the VA National CART Program of patients undergoing CA and PCI between 2010 and 2011 (n=28,513). Radiation exposure was measured using fluoroscopy time. We fit a mixed effects linear regression using log fluoroscopy time as outcome, a random effect for site, and adjusted for procedural and patient characteristics. Empirical Best Linear Unbiased Predictors for sites were used to estimate adjusted site level medians. The intra-class correlation (ICC) for site random effect was calculated to estimate the proportion of variance explained by site adjusting for patient and procedural characteristics. Marginal residuals were aggregated to site and examined at quarterly intervals for 2 years to establish stability of site medians over time.

Results:
Overall site median fluoroscopy time was 6 minutes (IQR: 3.5, 10.2) for CA and 16.5 (IQR: 10.3,26.1) minutes for PCI. After adjusting for procedural and patient characteristics, site median fluoroscopy times ranged from 43% below to 57% above the median for CAs and 66% below to 75% above for PCIs (Figure). Sites in the top quartile of fluoroscopy time were above the overall median in 96% for CA and 99% for PCI of time periods assessed. Cath lab site accounted for a significant amount of variance in fluoroscopy times (11.9% for CA and 21.5% for PCI).

Conclusion:
There is significant variation in fluoroscopy times across VA cath labs for coronary angiographies and PCIs. Even after adjustment for patient and procedures factors, there remains significant variability at the cath lab level suggesting that there may be opportunities for quality improvement interventions to reduce fluoroscopy times and radiation exposure for patients undergoing these procedures.
Abstract 18588: Baseline Neutrophil/Lymphocyte Ratio Predicts Recurrences After Radiofrequency Catheter Ablation: Results From Prospective Study on Paroxysmal Atrial Fibrillation
Authors: Trivedi Chintan , Di Biase Luigi , Mohanty Sanghamitra , Mohanty Prasant , Bai Rong , Santangeli Pasquale , Santoro Francesco , Hongo Richard , Beheiry Salwa , Horton Rodney , Sanchez Javier , Burkhardt J. David , Natale Andrea
Published: April 2024

Introduction:
Inflammation and atrial fibrillation (AF) are often associated. Whether Neutrophil Lymphocyte Ratio (NLR) affects the radiofrequency catheter ablation outcome is unknown. The aim of this study is to evaluate baseline NLR as the inflammatory predictor of ablation outcome in Paroxysmal AF (PAF) patients.

Method:
One hundred seventy five PAF patients undergoing radiofrequency catheter ablation were selected for the study and baseline hematological parameter were evaluated with differential cell count one day prior to ablation. All the patients underwent pulmonary vein antrum isolation and extensive follow-up.

Result:
Out of 165 patients with paroxysmal AF, 44 (25.1%) patients develop recurrence after average follow-up of 16 ± 8 months. Baseline NLR was high in recurrence patients. (NLR=3.2 ±0.6 vs. 2.59 ± 0.8, p<0.001). After adjusting for age,gender,coronary artey disease , LA Size and high blood pressure, baseline NLR was found to be a significant predictor of recurrence [HR =1.99 (1.33, 2.96), p=0.001]. Using the cut-off value of 3.08, baseline NLR predicts the recurrence with sensitivity of 72.5% and specificity of 78.6%.

Conclusion:
This prospective study shows that baseline NLR is useful inflammatory marker in predicting the recurrence of PAF and in patients with more than 3.08 baseline NLR have high chance of recurrence.
Abstract 18649: Tracking Spironolactone-Induced Regression of Myocardial Fibrosis and Myocyte Hypertrophy in Mice With Contrast-Enhanced Magnetic Resonance Imaging
Authors: Coelho-Filho Otavio R , Shah Ravi V , Neilan Tomas G , Mitchell Richard , Moreno Jr Heitor , Kwong Raymond Y , Jerosch-Herold Michael
Published: April 2024

Background:
In heart failure (HF) with preserved left ventricular ejection fraction, interstitial fibrosis and cellular hypertrophy are early markers of the adverse tissue remodeling in response to pressure-overload.

Methods:
Wild-type mice were assigned to three experimental groups: placebo (n=15), receiving tap water for 7 weeks; L-NG-Nitroarginine methyl ester (L-NAME) (n=22) (3mg/ml of L-NAME in drinking water, Sigma, USA) for 7 weeks; and L-NAME (3mg/ml) + spironolactone (n=21) (L-NAME-S), with spironolactone delivered by subcutaneous pellets at 50mg/kg/day. Extracellular volume (ECV) expansion, as a measure of interstitial fibrosis, and intracellular lifetime of water, τ
ic
, as a measure of cardiomyocyte hypertrophy, were assessed by pre and post-contrast T1 measurements. Minor (D
min
) and major (D
maj
) cell-diameters were measured on FITC-wheat germ agglutinin stained sections.

Results:
L-NAME without spironolactone increased mean arterial pressure (86.8±7.4 mmHg at baseline to 124.4±6.1 mmHg after 7 weeks of L-NAME therapy, P<0.001) and left venrtciular (LV) mass (162.9±19.4 μg for L-NAME vs. 98.5±14.4 μg for placebo,
P
<0.001), with a modest decrease in LV systolic function (LV ejection fraction 51.3±8.2% for L-NAME vs. 60.3±3.2% for placebo,
P
<0.001). Spironolactone reduced the mean arterial pressure and LV mass in L-NAME-treated mice. Spironolactone also reduced the myocardial ECV (0.43±0.09 for L-NAME vs. 0.25±0.03 for L-NAME+S, P<0.001), myocyte hypertrophy (τ
ic,
0.42±0.11 for L-NAME vs. 0.12±0.05 for L-NAME+S). The on-therapy effect of spironolactone on myocardial ECV and τ
ic
was observed even after adjustment for mean arterial pressure in linear regression (myocardial ECV: adjusted multiple R
2
= 0.71, P<0.001). ECV and τ
ic
had strong correlations with connective tissue fraction and cell size, measured by histology.

Conclusion:
CMR can track the progression and regression of interstitial fibrosis, cellular and LV hypertrophy in a murine model of hypertensive heart disease on exposure to spironolactone. This ability to non-invasively phenotype changes in cellular and tissue-based ventricular remodeling with therapy is critical to furthering our understanding of pathobiology of HF progression and its reversal.
Abstract 18657: Fibulin-4 Deficiency Alters Collagen Regulation in the Aortic Wall
Authors: Papke Christina L , Ringuette Lea-Jeanne , Yamashiro Yoshito , Tsunezumi Jun , Yamauchi Mitsuo , Davis Elaine , Yanagisawa Hiromi
Published: April 2024

Thoracic aortic aneurysms/dissections (TAAD) are a major cause of mortality each year in the U.S. Disruption of fibulin-4 (fbln4), an extracellular matrix component, leads to TAAD in human and mouse models. Fbln4 plays an essential role in elastic fiber assembly: our recent data suggest a role for proliferation in the aortic wall that may be independent of elastic fiber defects. Roles for Fbln4 beyond elastic fiber assembly have been suggested but not previously investigated. We hypothesize that Fbln4 loss alters the aortic wall microenvironment to promote localized cell proliferation, in part through altered collagen synthesis and maturation. Smooth muscle-specific Fbln4 deficient (SMKO) ascending aortas show increased BrdU+ cells at P30 (p<.05) localized throughout the aortic wall but mainly near the medial/adventitial border, irrespective of elastic fiber disruption. Smooth muscle actin inducible Cre mice show intact elastic fibers but a similar pattern of BrdU+ cells. Fbln4 loss also alters synthesis of collagen isoforms, leading to increased Type VIII mRNA (p<.05) and Type I protein expression. Electron microscopy, second harmonic generation images, and molecular analysis of collagen cross-linking revealed highly irregular collagen fiber bundle size, collagen fiber disorganization, and decreased mature cross-links (p<.05). Our data demonstrate a proliferative phenotype and previously uncharacterized collagen defect in Fbln4 deficient mice. Altered collagen isoforms and maturity are known to influence cell proliferation: future work will determine the precise identity of the proliferating cells and specific mechanisms by which collagen defects drive the proliferative phenotype. Increased understanding of the molecular mechanisms driving TAAD will ultimately lead to more effective treatments to delay or prevent onset of disease.
Abstract 18679: Abnormal Stress Induced Changes in Arterial Stiffness in Middle Aged Men and Women With Impaired Fasting Glucose at Risk of Their First Episode of Symptomatic Heart Failure
Authors: Vasu Sujethra , Morgan Timothy M , Kitzman Dalane W , Hamilton Craig A , Chiles Caroline , Soots Sandra , Thohan Vinay , Hundley W. Gregory
Published: April 2024

Background:
Abnormal arterial stiffness is associated with future heart failure (HF). We hypothesized that abnormal stress associated increase in arterial stiffness may be present in middle aged and elderly individuals with diabetes (DM) or the pre-diabetic state of impaired fasting glucose (IFG) that are at risk for their first episode of symptomatic HF.

Methods:
We analyzed dobutamine magnetic resonance stress imaging (DMRI) results from 373 consecutively recruited community dwelling individuals aged 55-85 years at risk for but yet to develop symptomatic HF, that had resting LVEF >45% and were without inducible ischemia. According to previously published techniques, personnel blinded to participant identifiers measured arterial stiffness (brachial pulse pressure/left ventricular stroke volume indexed to body surface area (PP/SVI) and the aortic elastance index or EaI (brachial end-systolic pressure/SVI) at rest and peak stress (80% of maximum predicted heart rate response for age). Participants were classified as normal fasting glucose (NFG), IFG or DM according to the ADA criteria.

Results:
Participants averaged 69 ± 8 years, were 79% white, 92% hypertensive and 66% women. After accounting for hypertension, gender, coronary artery disease, smoking, medications, dyslipidemia and visceral fat, we observed an abnormal paradoxical elevation in PP/SVI and EaI in those with IFG or DM aged 55 to 69 years; whereas in those ≥ 70 years, this abnormal increase was seen in all individuals regardless of their glucose state (Figure 1).

Conclusion:
Middle aged individuals with DM or the prediabetic state of IFG exhibit abnormal increases in arterial stiffness during dobutamine stress that is similar to elderly individuals’ ≥ 70 years at risk of their first episode of symptomatic heart failure. These data may help to explain why middle aged men and women with DM or IFG are predisposed to stress induced increase in episodic HF.
Abstract 18703: Fluorescence Tracking of Domain IV Voltage Sensor Motion Shows a Progressively Varying Molecular Phenotype in Long QT Syndrome Type 3 Mutants
Authors: Schubert Angela R , Asaro Alexandra B , Varga Zoltan , Silva Jonathan R
Published: April 2024

Background:
Long QT Syndrome type 3 (LQT3) is caused by mutations in SCN5a, which encodes the hNa
V
1.5 α subunit; each contains 4 domains (DI-DIV) with 6 transmembrane segments (S1-S6). S1-S4 form a voltage sensing domain (VSD) that transduces membrane potential into channel gating. The molecular mechanisms that lead to LQT3 and the consequences of mutation location remain unclear, and better definition will lead to improved phenotypic precision and therapeutic targeting. We use a recent technique, voltage-clamp fluorometry (VCF), to evaluate three LQT3 mutations in the DIV VSD: R1623Q, R1626P, and previously uncharacterized, S1609W.

Methods:
To track the S4, a cysteine was introduced into the DIV S3-S4 linker, and conjugated to a TAMRA-MTS label. mRNA was injected into
Xenopus
oocytes and currents and fluorescence were recorded after 3-5 days with cut-open VCF.

Results:
Activation, inactivation, and recovery were similar in WT and S1609W. R1626P activation and inactivation recovery was not significantly different from WT while inactivation was left shifted. Both mutants exhibited a pro-arrhythmic delay of inactivation onset at -30mV - S1609W by 44% (0.8 ms) and R1626P by 36% (0.7 ms), when compared to onset in WT (1.9 ± 0.0 ms). DIV S4 deactivation also differed significantly among WT, S1609W, and R1626P. Exponential fitting revealed two time constants for the WT DIV S4 to return to rest of 0.23 ms and 17.44 ms with magnitudes of 0.3 and 0.7 ± 0.1, respectively. In contrast, S1609W showed a significant increase in the fast component (0.8 and 0.2 ± 0.1). A single signal from R1626P showed an intermediate phenotype (0.7 and 0.3). Further, a delay in sensor deactivation onset observed in the WT was absent from both mutants. No fluorescence was detected from R1623Q, perhaps indicating an especially severe phenotype with respect to the DIV S4 motion.

Conclusion:
Fluorescent kinetics from two LQT3 mutants, S1609W and R1626P showed a progressive molecular phenotype in which a slow component of recovery to the resting state was impaired by the mutation. Comparison to ionic current inactivation revealed that the reduction in this slow component corresponded to an increase in the time to peak, implying that the onset of fast inactivation is delayed by these mutations.
Abstract 18743: Diagnostic and Prognostic Value of Gremlin-1 In Patients With Acute Congestive Heart Failure
Authors: Behnes Michael , Brueckmann Martina , Lang Siegfried , Ahmad-Nejad Parviz , Neumaier Michael , Borggrefe Martin , Hoffmann Ursula
Published: April 2024

PURPOSE:
Gremlin-1 is an inhibitor of bone morphogenetic proteins regulating cardiomyocyte formation. Gremlin-1 is involved in fibrotic and inflammatory processes and correlates with the degree of cardiac fibrosis. Congestive heart failure is characterized by an adverse structural remodelling of the myocardium. This study evaluates serum levels of Gremlin-1 in patients being suspected of acute congestive heart failure (aCHF) in the emergency department.

PATIENTS AND METHODS:
401 patients presenting with symptoms of acute dyspnea and/or peripheral edema in the emergency department were evaluated. Patients were followed up to five years after presentation in the emergency department. Blood samples for measurement of Gremlin-1 (Human Grem1 ELISA®, USCN Life Science Inc.), Osteopontin (OPN) (R&D Systems, Inc.) and NT-proBNP (Dimension System, Siemens AG) were collected at the initial clinical presentation.

RESULTS:
Median Gremlin-1 levels were significantly higher in patients with aCHF (291 ng/ml, n=122) as compared to patients without aCHF (205 ng/ml, n=279) (p=0.0001). Median Gremlin-1 correlated significantly with OPN (r=0.16, p=0.002) and NT-proBNP (r=0.24, p=0.001). Median Gremlin-1 levels were higher in patients with a left ventricular (LV) dysfunction (258 ng/ml, n=91) compared to patients with a normal LV function (221 ng/ml, n=135) (p=0.05). Median Gremlin-1 levels were higher in ACC/AHA class C/D patients (246 ng/ml, n=215) compared to class A/B patients (208 ng/ml, n=133) (p=0.02). Median Gremlin-1 levels were significantly higher in patients being rehospitalized because of aCHF (1 year: 477 ng/ml (n=34) vs. 215 ng/ml (n=367), p=0.0001; 5 years: 301 ng/ml (n=73) vs. 212 ng/ml (n=328); p=0.001) and in patients who died during follow-up (1 year: 255 ng/ml (n=57) vs. 218 ng/ml (n=344), p=0.04; 5 years: 229 ng/ml (n=129) vs. 210 ng/ml (n=272); p=0.08).

CONCLUSIONS:
Gremlin-1 serum levels were increased in patients suffering from aCHF. Gremlin-1 correlated with OPN, NT-proBNP, functional NYHA and structural AHA/ACC classification. Increased Gremlin-1 levels were associated with long-term aCHF related rehospitalization and all-cause mortality after 5 years.
Abstract 18756: Apelin is Crucial for the (Pro-Inflammatory) Activation of Endothelial Cells in Advanced Plaque Progression
Authors: Tempel Dennie , den Dekker Wijnand , Burgisser Petra , Pasterkamp Gerard , Cheng Caroline , Duckers Henricus
Published: April 2024

Recent findings have linked activation of endothelial cells (ECs) into a more pro-inflammatory phenotype with new vessel growth in atherosclerotic plaques, and plaque destabilization. Apelin signaling is a potent vascular regulatory pathway that mainly functions through ECs. Apelin levels are increased in human atherosclerotic lesions, but the effect of apelin on advanced atherosclerotic lesions remains unknown.

Apelin infusion in ApoE KO mice with advanced lesionsresulted in enhanced plaque vulnerability without altering the lesion size (
P
<0.01, n=10). Apelin proved to increase plaque neovascularization and hemorrhaging (
P
<0.05, n=10). In addition, apelin infusion resulted in endothelial expression of adhesion factors and cytokines, e.g. VCAM-1 and MCP1 (
P
<0.05, n=10).

In line,
in vitro
analysis demonstrated that apelin acts synergistically with the pro-inflammatory cytokine, TNFα, in enhancing the endothelial expression of adhesion factors and cytokines, including VCAM-1 and MCP1 (
P
<0.05, n=6) and loss of the endothelial barrier function (
P
<0.05, n=6)
.
In addition, apelin activates eNOS by phosphorylation and may thereby aggravating the pro-inflammatory state of the ECs, by ROS generation. For, apelin enhanced phosphorylated eNOS in cultured ECs under all conditions (
P
<0.05, n=6), whereas ROS production was only augmented by apelin when combined with TNFα (
P
<0.05, n=6).

We provide for the first time, evidence for the role of apelin in advanced plaque destabilization by promoting growth of the intraplaque vasculature and by activation of endothelial cells into a disease-prone phenotype.
Abstract 18777: Right Ventricular Outflow Tract Strain is Reduced in Tetralogy of Fallot Compared to Valvar Pulmonary Stenosis Patients; Regional RV Function Defined by Strain Cardiac Magnetic Resonance Imaging
Authors: Anwar Shafkat , Harris Matthew A , Whitehead Kevin K , Keller Marc S , Fogel Mark A , Mercer-Rosa Laura M
Published: April 2024

Introduction:
The right ventricular outflow tract (RVOT) patch after Tetralogy of Fallot (ToF) surgery may contribute to ventricular dysfunction, but the specific effects on RV function are not clear. We aimed to investigate RV function in patients with ToF and RVOT patch by comparing to patients with valvar pulmonary stenosis (vPS) after balloon valvuloplasty (no RVOT patch).

Methods:
We conducted a retrospective review of 33 CMR studies of ToF and vPS patients with similar pulmonary regurgitation (PR) Table 1. Feature tracking strain (FTS) analysis of balanced steady state free precession (SSFP) cines was performed on the RV in apical 4-chamber (4ch), RVOT sagittal & mid-RV short axis views (TomTec 2D Cardiac Performance Analysis, v1.0), Figure 1. Unpaired t-tests were applied for comparison of means between groups.

Results:
Lagrangian longitudinal strain (LS) at the RVOT was significantly lower in ToF compared to vPS (mean -14.1% vs -18.2%, unpaired t-test p = 0.03), Table 1. Analysis of regional S within the same group showed a trend towards lower RVOT strain compared to 4ch LS in ToF (p = 0.052). There were no significant inter-group differences in strain from the 4ch or mid-RV short axis views, with normal 4ch LS in both groups.

Conclusion:
In a population with preserved EF, RVOT strain is significantly lower in ToF patients with a transannular patch compared to vPS patients with similar amount & duration of PR. Low RVOT LS appears to be a regional phenomenon, with strain in the 4ch and mid-RV similar between groups. Further investigation is warranted in a larger sample. FTS analysis is a promising technique to evaluate regional RV mechanics in this population.