bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11808: Association Between Left Ventricular Properties in Patients With Hypertension and the Incidence of Paroxysmal Atrial Fibrillation: Three-Dimensional Speckle Tracking Echocardiographic Study
Authors: Kawade Masafumi , Kawasaki Masanori , Minatoguchi Shingo , Tanaka Ryuhei , Ishiguro Maya , Sato Noriaki , Nagaya Maki , Kaneda Mayumi , Yagasaki Hiroto , Goto Yoshiaki , Iwama Makoto , Hirose Takeshi , Ono Koji , Arai Masazumi , Noda Toshiyuki , Watanabe Sachiro , Minatoguchi Shinya
Published: July 2021

Background:
Hypertension (HTN) is one of the major causes of atrial fibrillation (AF), since it is usually accompanied by left atrial (LA) remodeling due to pressure and/or volume (LAV) overload. We examined the relationship between ventricular (LV) geometry or LV properties in HTN and the incidence of paroxysmal AF (PAF) using novel, one-beat, automated, 3-dimensional speckle tacking echocardiography (3D-STE) with high volume rates.

Methods:
Patients with HTN (n=107, age 69±7) and controls (n=60, age 69±9) were prospectively enrolled. HTN patients were divided into 5 groups according to LV geometry and the presence of hypertensive heat failure (HHF) {normal geometry (n=25), concentric remodeling (n=20), concentric hypertrophy (LVH) (n=24), eccentric LVH (n=21) and HHF (n=17)}. Isovolumic relaxation time (IVRT) was measured by Doppler echo. We evaluated LV ejection fraction (EF), E/e’, pulmonary capillary wedge pressure (PCWP), Tau, LV diastolic stress, LV strain and LV myocardial stiffness in sinus rhythm. PCWP was estimated as 10.7- 12.4 x log (LA active emptying function / minimum LAV) as we reported. Tau was calculated as IVRT / (ln 0.9 x systolic blood pressure - ln PCWP). LV diastolic stress was calculated as LV radius at end diastole x PCWP / thickness. LV strain rate (SR) during IVR, as an index of relaxation, and LV strain were measured by the 3D-STE with volume rates of 50-80vps. LV myocardial stiffness was estimated as LV stress / LV strain.

Results:
LVEF was reduced only in HHF compared with controls (56±7 vs. 67±6%).

Conclusion:
LVEF in HHF was decreased but still remained within the normal range, whereas diastolic properties in eccentric LVH and HHF were reduced compared with control. The incidence of PAF significantly increased in eccentric LVH and HHF associated with the impairment of LV relaxation and stiffness and increased LV stress. This suggests that the target of treatment to reduce the incidence of PAF in HTN must be diastolic function.
Abstract 11866: Left Ventricular Diastolic Function Assessed by Echocardiography and Tissue Doppler Imaging is a Strong Predictor of Cardiovascular Events in Patients With Diabetes Mellitus Type 2
Authors: Blomstrand Peter , Engvall Martin , Festin Karin , Lindstrom Torbjorn , Lanne Toste , Maret Eva , Nystrom Fredrik , Ouda John , Ostgren Carl-Johan , Engvall Jan E
Published: July 2021

Aims:
The aim of the study was to evaluate the independent role of left ventricular systolic function in terms of global longitudinal strain, and diastolic function expressed as the ratio between early diastolic transmitral flow- and mitral annular motion velocities (E/é) in predicting cardiovascular events in patients with diabetes mellitus type 2.

Methods:
We prospectively investigated 406 consecutive patients, aged 55-65 years, with diabetes mellitus, who participated in the CARDIPP study. Echocardiography, carotid intima media thickness, carotid-femoral pulse wave velocity, pulse pressure measurement (pp) and glycosylated hemoglobin (HbA1c) were analysed.

Results:
Twelve cases of myocardial infarction and seven cases of stroke were identified during the follow-up period of 67 ± 17 months. Univariate Cox regression analysis showed that E/é was a strong predictor of cardiovascular events (HR 1.12; 95 % CI 1.06 to 1.18, p < 0.001) and in a multivariate analysis E/é was prospectively associated with cardiovascular events independent of age, sex, global longitudinal strain, pulse wave velocity, carotid intima media thickness, pp and HbA1c. The addition of HbA1c and pp to E/é increased the predictive value of the model significantly, [(E/é vs. E/é + HbA1c vs. E/é + HbA1c + pp) χ
2
= 18.1 vs. χ
2
= 23.0 vs. χ
2
=30.0, p = 0.030 vs. p = 0.007], but global longitudinal strain did not. An elevated E/é ratio, defined as > 15, was also predictive of major cardiovascular events in a Kaplan-Meyer analysis. The cumulative probability of the development of an event during the follow-up period for patients with an E/é ratio > 15 was 8.6 % compared with 2.6 % for patients E/é ratio ≤ 15, p = 0.021.

Conclusion:
Left ventricular diastolic dysfunction expressed as E/é is a strong predictor of myocardial infarction and stroke in middle-aged patients with diabetes mellitus, superior to global longitudinal strain, arterial stiffness and carotid intima media thickness.
Abstract 11877: Novel Method to Quantify the Degree of Fluid Accumulation and Its Prognostic Implication in Patients With Acute Decompensated Heart Failure
Authors: Sakaguchi Taiki , Yasumura Kaori , Nishida Hiroki , Inoue Hiroyuki , Furukawa Tetsuo , Shinouchi Kazuya , Miura Hiroyuki , Miyazaki Koichi , Koide Masao , Abe Haruhiko , Hirooka Keiji , Koretsune Yukihiro , Kusuoka Hideo , Yasumura Yoshio
Published: July 2021

Introduction:
Fluid accumulation is an important therapeutic target in acute decompensated heart failure (ADHF). Our objective was to develop a non-invasive and repeatable clinical method to quantify the degree of fluid accumulation in ADHF patients, and investigate its prognostic implications.

Methods:
We measured extracellular water (ECW) volume using bioelectrical impedance analysis (BIA) in 60 control subjects without heart failure (aged 75±7 years). The reliability of the measured values was assessed through comparisons with ECW estimates from Moore’s regression equations based on multiple isotope dilution. We then developed original regression equations to predict ECW values from multivariate analyses that incorporate patient height, body weight, age and sex. ECW values on admission and at discharge in 120 ADHF patients (aged 73±11 years) were measured, and the ratios of measured to predicted ECW values (M/P ratios) were calculated. The primary endpoint was the occurrence of cardiac death or readmission for ADHF.

Results:
In the control subjects, BIA-measured ECW values correlated with those estimated by Moore’s equations (r
2
=0.72, p<0.001), and showed even stronger correlations with estimates from our equations (r
2
=0.86, p<0.001). In ADHF patients, measured ECW was significantly reduced during hospitalization (15.4±6.2L to 12.1±4.7L, p<0.001), and M/P ratios were approximately 100% at discharge (126±26% to 104±19%, p<0.001). Patients whose M/P ratios remained higher than 100% at discharge showed higher 3-month cardiac death or readmission rates than patients with lower M/P ratios (50% vs 17%, hazard ratio 3.69; 95% confidence interval 1.935-7.048, p<0.001).

Conclusions:
We successfully quantified the degree of fluid accumulation using BIA, and the predicted ECW estimates from our regression equations can be a treatment goal in ADHF patients. This BIA-guided therapy may provide better clinical outcomes in the management of ADHF.
Abstract 11889: Phase Ib Study of Icosabutate, a Novel Structurally Enhanced Fatty Acid, in Subjects With Hypercholesterolemia
Authors: Qin Yan , Hallén Jonas , Skjæret Tore , Odden Erling , Fraser David , Nyheim Hilde , Cornelissen Karen , Chiesa Joseph , Hustvedt Svein Olaf
Published: July 2021

Introduction:
Icosabutate, an orally active structurally enhanced fatty acid (SEFA), has demonstrated reductions in triglycerides (TG) and cholesterol in several rodent models of dyslipidemia and diabetes. In clinical single and multiple ascending dose studies, icosabutate was well tolerated and significantly lowered LDL-C, non-HDL-C, and TG in subjects with mixed dyslipidemia. This phase 1b study explored the lipid-lowering effects of icosabutate in subjects with hypercholesterolemia.

Methods:
This was a randomized, double-blind, placebo-controlled study. Subjects with hypercholesterolemia treated with a statin for at least 3 months were screened. Statins were temporarily discontinued for at least 28 days prior to dosing and for the duration of the study. To qualify for the study, subjects were required to have an LDL-C ≥ 2.5 mmol/L (97 mg/dL) at the secondary screening visit and an increase in LDL-C of at least 20 % between the primary and secondary screening. Twenty four subjects were randomized to icosabutate 600 mg once daily or matching placebo in a 3:1 fashion and treated for 28 days. Safety and pharmacodynamics were evaluated. Results are reported as placebo-adjusted median percentage change from baseline (average of visit 2-4) to 24 hours after last dose (day 29).

Results:
Six subjects received placebo and 18 subjects received icosabutate. Median baseline lipid values (mg/dL) placebo/ icosabutate: TC: 270 and 240; LDL-C: 174 and 166; and TG: 204 and 168. Compared to placebo, icosabutate reduced total cholesterol (17.4 %, p < 0.05), LDL-C (29.3 %, p<0.05), non-HDL-C (25.4 %, p<0.05), and apo B (22.8 %, p< 0.05). There was a non-significant increase in HDL-C. TG reductions were not statistically significant (12.6 %, ns), but both placebo and icosabutate subjects experienced large reductions from baseline (29 % versus 42 %).

Conclusions:
In this randomized, double-blind, placebo-controlled phase Ib study in subjects with hypercholesterolemia, icosabutate demonstrated placebo-adjusted reductions in total cholesterol, LDL-C, non-HDL-C, and apo B. TG levels were also substantially reduced, but not statistically significant in placebo-adjusted analyses.
Abstract 11898: Effects of Insulin Glargine on Left Ventricular Mass and Function in Patients With Dysglycemia
Authors: Haroun Michelle , Leong Darryl P , Dokainish Hisham , Bosch Jackie , Diaz Rafael , Yusuf Salim , Gerstein Herztel C , Lonn Eva ,   The ORIGIN Investigators
Published: July 2021

Introduction:
Type 2 diabetes mellitus (T2DM) is associated with increased risk for left ventricular (LV) hypertrophy and heart failure (HF). Moreover, some drugs used to treat hyperglycaemia are associated with increased risk of HF. There are limited data on the effects of exogenous insulin on left ventricular mass (LVM) and function (LVF). Therefore, we evaluated the effects of insulin glargine on LVM and LVF in the echocardiographic substudy of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784).

Methods:
Patients aged ≥ 50 years with dysglycemia (early T2DM, impaired glucose tolerance, or impaired fasting glucose) and with cardiovascular (CV) disease or CV risk factors were randomized to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard glycemic care. Echocardiograms were performed at baseline and after 3 years. Changes in LVM, LV ejection fraction (LVEF), wall motion score (WMS), LV end-diastolic and end-systolic volume (LVEDV and LVESV), E/A, and E/E’ were compared between the study groups using mixed effects modelling.

Results:
564 patients aged 64 ± 8 years were evaluated; 30% were women, 84% had a history of hypertension and 32% of prior myocardial infarction. This is the largest reported study on the effects of exogenous insulin on LVM and LVF. There were no significant differences in the changes over time in LVM and LV systolic and diastolic function between the study groups (Table).

Conclusions:
In people with CV disease and/or CV risk factors and dysglycemia three years of treatment with insulin glargine has a neutral effect on LVM and on LV systolic and diastolic function. These findings support the CV safety of insulin glargine.
Abstract 11947: Unraveling the Mechanism for the Stimulatory Role of Platelet GPIb-IX-V in Thrombin-Induced Platelet Activation
Authors: Estevez Brian , Delaney Michael K , Stojanovic-Terpo Aleksandra , Du Xiaoping
Published: July 2021

Numerous reports indicate that the platelet glycoprotein (GP) Ib-IX complex (GPIb-IX) binds directly to the potent platelet agonist thrombin and is important for promoting thrombin-induced platelet activation. However, how GPIb-IX contributes to thrombin-induced platelet activation is unclear. It has been suggested that thrombin binding to GPIb facilitates the cleavage, and thus activation, of the protease-activated receptors (PAR). Our data indicate that GPIb-IX promotes thrombin signaling through a GPIb-IX signaling mechanism. Pretreatment of human platelets with MPalphaC, an inhibitory peptide based on a critical 14-3-3 signaling protein binding site on the cytoplasmic domain of the GPIb alpha chain, inhibited thrombin-induced platelet activation. MPalphaC-treatment inhibited thrombin-induced activation of Rac1 and LIMK1, both of which are known to play essential roles in GPIb signaling. To more specifically determine the role of GPIb-IX, we reconstituted GPIb-IX-facilitated thrombin signaling in Chinese Hamster Ovary cells expressing PAR1. Thrombin induced signaling was significantly enhanced by GPIb-expression, and deletion of the cytoplasmic 14-3-3-binding domain of GPIb alpha abolished the stimulatory effect of GPIb on thrombin signaling. Furthermore, the role of GPIb-IX in promoting thrombin signaling requires Rac1, and GPIb-IX-dependent Rac1 activation and LIMK phosphorylation are abolished in delta 605 cells expressing a 14-3-3-binding defective mutant GPIb alpha. Taken together, these data suggest that the stimulatory role of GPIb in thrombin signaling requires a C-terminal 14-3-3-binding region which mediates activation of a Rac1/LIMK1 pathway that promotes thrombin signaling leading to platelet activation.
Abstract 12008: Nos1 Adapter Protein Nos1ap Overexpression Alters Qtc Intervals in Transgenic Mice
Authors: Williams Tatjana , Arias-Loza Anahi P , Abeßer Marco , Schmitt Joachim , Schuh Kai , Ritter Oliver
Published: July 2021

Background:
Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders.

Methods and Results:
We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions.

However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression.

We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans.

Conclusion:
Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.
Abstract 12044: Absence of Coronary Artery Disease by Coronary Computed Tomographic Angiography and the Warranty Period Associated With All-Cause Mortality: Findings From the CONFIRM Long-Term Follow-Up Registry
Authors: Cho Iksung , ó Hartaigh Bríain , Gransar Heidi , Schulman-Marcus Joshua , Valenti Valentina , Berman Daniel S , Budoff Matthew J , Achenbach Stephan , Al-Mallah Mouaz , Andreini Daniele , Cademartiri Filippo , Callister Tracy Q , Chang Hyuk-Jae , Chinnaiyan Kavitha , Cury Ricardo , Delago Augustin , Gomez Millie , Hadamitzky Martin , Hausleiter Joerg , Hindoyan Niree , 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:
Coronary computed tomographic angiography (CCTA) is widely utilized for the detection of coronary artery disease (CAD). Foremost, the very low risk associated with normal CCTA is an important component for the purpose of cardiovascular risk stratification. To date, however, data that accounts for long-term prognosis of normal CCTA is sparse.

Purpose:
Using data from a multi-center, global observational CCTA registry, we sought to determine the potential warranty period of normal CCTA.

Methods:
Among 12,086 patients who underwent CCTA, 7,651 patients without history of previous CAD, aged between 30-74 years, were included in the current analysis and followed consecutively over 5 years. Normal CCTA was defined as the absence of any plaque in the coronary arteries. Annual mortality was calculated and compared with overall patients. The primary event in this study was all-cause mortality (ACM).

Results:
During a median follow-up of 5.8 years (IQR, 5.3-6.3 years), 120 of all-cause deaths occurred among 3,051 patients with normal CAD. Mean age of the study population was 52±11 years, and 45% were men. Annual mortality rate was 0.68% (95% confidence interval (CI), 0.57~0.82), while annual mortality of overall patients was 1.31% (95% CI, 1.20~1.42) (
p
<0.001). When we defined warranty period as a follow-up duration until the estimated mortality reached the threshold of 5% using a Kaplan Meier curve, the warranty period of normal CCTA for ACM was 7.2 years. In subgroup analysis, according to a baseline risk factor profile using Framingham risk scores (FRS), annual mortality rate was 1.31% (95% CI, 0.85~2.03) among patients with high FRS and 0.62% (95% CI, 0.51~0.76) among those with low to intermediate FRS.

Conclusion:
Absence of CAD by CCTA demonstrates a favorable survival rate with a minimum warranty period of at least 7 years. Persons presenting with a high cardiovascular risk profile displayed a relatively higher mortality, which is similar to overall population. Therefore, they should be considered a distinct group of individuals at-risk by physicians and researchers alike.
Abstract 12088: cMyBP-C’S Interaction With Actin is Critical to Maintain Diastolic Function in vivo
Authors: Bhuiyan Md. Shenuarin , James Jeanne , Osinska Hanna , Gulick James , Lorenz John N. , Robbins Jeffrey
Published: July 2021

Background:
cMyBPC’s interaction with actin is critical to maintain diastolic function
in vivo

Rationale:
Extensive studies demonstrate that cardiac myosin binding protein C (cMyBP-C) is a critical mediator of diastolic function through its interaction with actin, myosin and titin. The precise molecular mechanisms underlying the protein’s function remain elusive as cMyBP-C’s structural domains responsible for actin and/or myosin interaction are ill-defined and the physiological consequences of these filament interactions are unknown.

Objective:
In the present study, we made transgenic mice that lacked cMyBP-C’s actin and/or the head region of the myosin heavy chain (S2-MyHC) sites in order to better understand the molecular mechanisms of cMyBPC-mediated regulation of cardiac contraction, particularly diastolic function.

Methods and Results:
Using a combination of genetics and functional assays, we defined cMyBP-C’s N-terminal structural domains as well as the critical residues necessary or sufficient to mediate interactions with actin and/or S2-MyHC. Using genetic experiments, we first confirmed that mutation of three lysines to alanines in the C1 domain abolished actin binding (cMyBP-C
Act-
). Similarly, mutation of three arginines to alanines in the “m” domain abolished S2-MyHC binding (cMyBP-C
S2-
). To determine the functional roles of these sites in vivo, we generated transgenic lines in which normal cMyBP-C was replaced by either cMyBP-C
Act-,S2-
or wild type (cMyBP-C
WT
), transgenically-encoded cMyBP-C. Mutant protein was completely substituted for endogenous cMyBP-C by breeding the transgenes into a cMyBP-C null background. The cMyBP-C
Act-,S2-
mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis. Echocardiographic Doppler measurements showed that cMyBP-C
Act-,S2-
mice develop both diastolic and systolic dysfunction. In contrast, the cMyBP-C
WT
Tg line showed normal cardiac structure and function.

Conclusions:
These results suggest that the cMyBP-C’s interactions with both actin/S2-MyHC are structurally important to preserve normal cardiac contractility and particularly, cMyBP-C’s interaction with actin is indispensable for normal diastolic function.
Abstract 12138: Angiotensin Blockade Reduces Aortic Dilatation in Patients With Marfan Syndrome: A Meta-Analysis
Authors: Sardar Partha , Kundu Amartya , Adenikinju Omosalewa , Pekler Gerald , Chatterjee Saurav , Krishnamoorthy Parasuram , Aronow Wilbert S
Published: July 2021

Introduction:
Recently few studies evaluated the effects of ACE/ARB in patients with Marfan syndrome. However, as majority of the studies were small and mainly pilot studies, conclusive evidence of benefit with ACE/ARB in this scenario is still pending. The objective of the present meta-analysis was to evaluate the effect of ACE/ARB on the progression of aortic root dilatation in patients with Marfan syndrome.

Hypothesis:
Treatment with ACE/ARBs is effective for the prevention of aortic-root enlargement in patients with Marfan syndrome.

Methods:
We searched PubMed, EMBASE, and Cochrane Central Register of Clinical Trials from the inception to April 30, 2013. The main outcome of the present analysis was the change in aortic root diameter with ACE/ABR therapy compared to control. The random effects model of DerSimonian and Laird was used.

Results:
Four studies were included in the final analysis; three studies were randomized trial and one was observation study. ACE/ARB significantly reduced enlargement of aortic root diameters compared to control; mean difference of -0.97 (95% confidence interval, -1.42 to -0.52; P<0.0001). Consistent benefit of ACE/ARB was observed in all sub-group and sensitivity analyses; against beta blocker, against placebo, in adult patients, with only ARB, analysis with the results from only RCTs.

Conclusions:
This is the first meta-analysis indicating a beneficial effect of ACE/ARB treatment on aortic root dilatation in patients with Marfan Syndrome. Current evidence supports the use of ARB, specially losartan for this indication.
Abstract 12192: MBNL1 Directly Regulates the Alternative Splicing of mRNAs That Promote Myofibroblast Differentiation
Authors: Davis Jennifer , Sargent Michelle , Shi Jianjian , Wei Lei , Swanson Maurice S , Molkentin Jeffery D
Published: July 2021

Rationale:
During the cardiac injury response fibroblasts differentiate into myofibroblasts, a cell type that enhances extracellular matrix production and facilitates ventricular remodeling. To better understand the molecular mechanisms whereby myofibroblasts are generated in the heart we performed a genome-wide screen with 18,000 cDNAs, which identified the RNA-binding protein muscleblind-like splicing regulator 1 (MBNL1), suggesting a novel association between mRNA alternative splicing and the regulation of myofibroblast differentiation.

Objective:
To determine the mechanism whereby MBNL1 regulates myofibroblast differentiation and the cardiac fibrotic response.

Methods and Results:
Confirming the results from our genome wide screen, adenoviral-mediated overexpression of MBNL1 promoted transformation of rat cardiac fibroblasts and mouse embryonic fibroblasts (MEFs) into myofibroblasts, similar to the level of conversion obtained by the profibrotic agonist transforming growth factor β (TGFβ). Antithetically,

Mbnl1
-/-

MEFs were refractory to TGFβ-induced myofibroblast differentiation. MBNL1 expression is induced in transforming fibroblasts in response to TGFβ and angiotensin II. These results were extended
in vivo
by analysis of dermal wound healing, a process dependent on myofibroblast differentiation and their proper activity. By day 6 control mice had achieved 82% skin wound closure compared with only 40% in

Mbnl1
-/-

mice. Moreover,

Mbnl1
-/-

mice had reduced survival following myocardial infarction injury due to defective fibrotic scar formation and healing. High throughput RNA sequencing (RNAseq) and RNA immunoprecipitation revealed that MBNL1 directly regulates the alternative splicing of transcripts for myofibroblast signaling factors and cytoskeletal-assembly elements. Functional analysis of these factors as mediators of MBNL1 activity is also described here.

Conclusions:
Collectively, our data suggest that MBNL1 coordinates myofibroblast transformation by directly mediating the alternative splicing of an array of mRNAs encoding differentiation-specific signaling transcripts, which then alter the fibroblast proteome for myofibroblast structure and function.
Abstract 12259: Epidemiology of Valvular Heart Diseases: A 30-Year Retrospective of Hospitalizations and In-Hospital Mortality in New York State
Authors: Supino Phyllis G , Hai Ofek Y , Khan Nasimullah , Borer Jeffrey S
Published: July 2021

Background:
Valvular heart disease (VHD) is among the most predictable causes of heart failure (HF) and an important cause of sudden death. Temporal trends of clinically significant VHD during the past three decades have not been defined.

Methods:
To obtain information for our region, we conducted a longitudinal analysis of all inpatient hospital records (79,689,879) obtained from the New York State (NYS) Statewide Planning and Research Cooperative System (SPARCS) database for years 1983 (first year reliable data were consistently available) through 2012 (last year data were complete). VHD cases (2,720,313) were identified from principal or secondary ICD-9 codes for aortic, mitral, tricuspid or pulmonic VHD. Linear regression was used to evaluate trends over time for VHD hospitalizations, valve surgery (VS) and in-hospital deaths. Logistic regression was used to predict mortality risk factors.

Results:
From 1983-2012, total hospitalizations decreased by ~500,000 cases; simultaneously, VHD hospitalizations increased markedly (34,395 in 1983 to 125,139 in 2012). Rate of increase was linear across all VHD categories = 4,248 new cases (12.4%)/yr, r
2
= 0.99, p<.0001) through 2006 (peak= 132,323 cases), and then flattened through 2012. A parallel trend was found for VS, though no appreciable flattening occurred (2,582 cases in 1983 to 7,787 in 2012, linearized increase rate=207 VS [8.0%]/yr, r
2
=0.97, p<.001). Both numbers of hospitalizations and performance of VS rose with patient age (p<.001). Over the study interval, 123,787 patients with VHD died in the hospital, including 9,272 who died after VS; avg case fatality rates were 4.6% (all VHD) and 6.4% (VS). Deaths were independently associated with advancing age, nonelective admission and presence of associated HF (p<.0001, all). Male gender predicted increased death risk among the general VHD population; female gender predicted death risk among those undergoing VS.

Conclusions:
The incidence of VHD hospitalization and VS in NYS has risen substantially since the early 1980s and can be expected to rise further as the population ages. Thus, intensive planning is needed to deal with public health implications of these trends as we attempt to meet the growing needs of this patient population.
Abstract 12271: Radiofrequency Ablation With Electrode in Contact With Circular Mapping Catheter: Coagulation, Char, and Pop Ocurrence Comparison With Two Types of Irrigated Ablation Catheters
Authors: Oberti Carlos , Ashton John , Birchard Christopher , Wazni Oussama , Saliba Walid
Published: July 2021

Introduction:
A circular mapping catheter (CMC, Biosense Webster Lasso® Catheter) is frequently used in radiofrequency (RF) ablation treatment of atrial fibrillation to aid in determining ablation targets, such as the pulmonary vein ostia. During RF delivery, the ablation electrode is often in close proximity and may sometimes be in contact with one of the electrodes of the CMC. In this study, we compare coagulation, tissue char, and pop occurrence for ablations in contact with a CMC electrode versus ablations without a CMC. Ablations were performed with open-irrigation ablation electrodes of the Biosense Webster ThermoCool® Catheter (6 hole) and ThermoCool® SF Catheter (56 hole).

Hypothesis:
There will be more coagulation formation when there is contact with CMC.

Methods:
The thigh muscles of 4 anesthetized pigs were exposed and a skin cradle created. A 6 hole or 56 hole catheter was placed on the muscle with 10g of force in perpendicular orientation. Some ablations were performed with the ablation catheter alone, while others were performed with a CMC resting on the thigh muscle and the ablation electrode contacting one of the CMC electrodes on top or on the side. Heparinized autologous blood (activated clotting time > 350s) at 37°C was circulated in the thigh cradle at 275-300ml/min while ablations were performed at 50W for 60s with 30ml/min irrigation for 6 hole and 15ml/min for 56 hole. Pops during ablation were noted. After the ablation, the blood pool was removed while keeping the catheters in position, the ablation site was examined, and coagulation and tissue char was noted

Results:
See Table

Conclusions:
When comparing ablations with a CMC versus no CMC, there was more coagulation with a CMC. When comparing a 6 hole catheter with a CMC versus a 56 hole catheter with a CMC, there was more coagulation with the 6 hole ablation catheter. There was no significant difference in pop and tissue char in any comparison
Abstract 12306: Changes of Metabolomic Profiling Are Associated With Reduced Exercise Capacity in Patients With Heart Failure
Authors: Tsuda Masaya , Kinugawa Shintaro , Fukushima Arata , Matsushima Shoji , Furihata Takaaki , Takada Shingo , Kadoguchi Tomoyasu , Kudo Masato , Matsumoto Junichi , Yokota Takashi , Okita Koichi , Tsutsui Hiroyuki
Published: July 2021

Background:
Exercise intolerance is a major clinical manifestation, and closely related to poor prognosis in heart failure (HF) patients. Metabolic derangements have been shown to play an important role in this phenomenon. Recent metabolomic investigations have highlighted several novel biochemical pathways in HF, however, metabolic profiling associated with exercise capacity has not been elucidated. We thus investigated the metabolites associated with exercise capacity by using global metabolomic analysis of plasma samples in HF patients.

Methods:
Ten consecutive HF patients with reduced ejection fraction (57 ± 12 years old, New York Heart Association class II - III) and 5 age-matched healthy subjects as controls (56 ± 3 years old) were studied. Charged metabolites in plasma samples were measured by capillary electrophoresis mass spectrometry. Peak oxygen uptake (peak VO
2
) and VE/VCO
2
slope were measured by cardiopulmonary exercise test.

Results:
A total of 233 charged metabolites were identified and quantified absolutely using standard chemicals for each metabolite. Significant increases in arginine methylation, phospholipid metabolites, and urea cycle metabolites were observed in HF patients compared to controls (Figure). Peak VO
2
was negatively correlated with methylarginine including asymmetric dimethylarginine (ADMA) (r=-0.77, P<0.001) and symmetric dimethylarginine (SDMA) (r=-0.65, P=0.040) levels, and phospholipid metabolites including choline (r=-0.63, P=0.049) and
N,N
-dimethylglycine (r=-0.75, P=0.011) levels in HF patients. VE/VCO
2
slope was positively correlated with
N,N
-dimethylglycine (r=0.72, P=0.026) and Urea (r=0.82, P=0.006) levels.

Conclusions:
Increases in metabolites of arginine methylation, phospholipid metabolism, and urea cycle were associated with exercise intolerance in HF. These results provide mechanistic insights into exercise intolerance associated with HF.
Abstract 12315: Four-and-a-Half LIM Domain Protein-2 Absence Reduces Atherogenesis in Apolipoprotein E-deficient Mice: Role of Monocytic Immune Cells
Authors: Ebrahimian Talin , Simon David , Simeone Stefania , Lemarié Catherine A , Heidari Maryam , Mann Koren , Lehoux Stéphanie , Wassmann Sven
Published: July 2021

Background:
Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial and vascular smooth muscle cells. It negatively regulates endothelial cell survival and migration, but its role in atherogenesis is unknown.

Methods and Results:
FHL2-deficient (FHL2-/-) mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice to generate ApoE/FHL2-/- mice. After high-fat, high-cholesterol diet, ApoE/FHL2-/- mice displayed significantly smaller atherosclerotic plaques than ApoE-/- mice in the aortic sinus, the brachiocephalic artery and the aorta. This was associated with significantly enhanced collagen and smooth muscle cell contents and a significant 2-fold reduction of macrophage content within the plaques of ApoE/FHL-2-/- vs ApoE-/- mice. There was a significant reduction in aortic ICAM-1 mRNA and VCAM-1 protein expression in the plaques of ApoE/FHL2-/- mice. Aortic gene expression of CX3CL1 and CCL5 was significantly increased in ApoE/FHL2-/- vs ApoE-/- mice. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of pro-inflammatory Ly6C-high monocytes were recruited in ApoE/FHL2-/- vs ApoE-/- mice. Furthermore, mRNA levels of CX3CR1 were 2-fold higher in monocytes from ApoE/FHL2-/- vs ApoE-/- mice. Finally, we investigated the potential importance of myeloid cell FHL2 deficiency in atherosclerosis. After being irradiated, ApoE-/- or ApoE/FHL2-/- mice were transplanted with ApoE-/- or ApoE/FHL2-/- bone marrow. After high-fat, high-cholesterol diet, both chimeric groups developed significantly smaller plaques than ApoE-/- mice transplanted with ApoE-/- bone marrow.

Conclusion:
These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherogenesis by promoting pro-inflammatory chemokine production, adhesion molecule expression, and pro-inflammatory monocyte recruitment.
Abstract 12391: High Density Lipoprotein in Coronary Artery Disease Impairs Vascular Endothelial Growth Factor- Induced Angiogenesis
Authors: Ou Jingsong , Chang Feng-Jun , Ou Zhi-Jun , Hu Xiao-Xia , Wu Jia-Yun , Yuan Hai-Yun , Dong Yu-Gang , Wang Zhi-Ping , Zhang Xi , Wang Shen-Ming
Published: July 2021

Aims:
Previous clinical trials designed to stimulate coronary vascular growth (therapeutic angiogenesis) using growth factors, e.g, vascular endothelial growth factor (VEGF), in patients with coronary artery disease (CAD) were unsuccessful. Although many reasons were postulated for the failure, e.g., endothelial dysfunction, refractory response to VEGF, no consensus was achieved to explain these unsuccessful attempts. To further interrogate this conundrum, we found that high density lipoprotein from healthy subjects (nHDL) is pro-angiogenic; however, HDL from patients with CAD (pHDL) has oxidative modifications. Accordingly we postulate that this modified pHDL is proinflammatory and “switches” to an anti-angiogenic effect. To test this possibility we determined the angiogenic capacity of pHDL and of pHDL on VEGF induced-angiogenesis.

Methods and Results:
Human umbilical vein endothelial cells (HUVECs) were cultured; murine hearts were isolated and sectioned, and the sections were cultured under condition in which endothelial cells sprout from the sections. HUVECs and the heart sections were treated with nHDL (100 μg/ml) or pHDL (100 μg/ml) with or without VEGF stimulation. We measured proliferation, migration, tube formation of HUVECs, and number and length of sprouts from the sections. pHDL (compared to nHDL) reduced endothelial cell proliferation, migration, tube formation, and the length of the sprouts from the sections under basal conditions and also in response to VEGF (all P<0.05). To elucidate the mechanism of this negative effect of pHDL, we measured nitric oxide (NO) production, superoxide anion (O2[[Unable to Display Character: ˙]]
−
) generation, phosphorylation of endothelial nitric oxide synthase (eNOS), and Akt in HUVECs. Compared to nHDL, pHDL reduced the phosphorylation of eNOS, and Akt; and, also inhibited NO production, but increased eNOS-dependent O2[[Unable to Display Character: ˙]]
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generation.

Conclusions:
HDL from patients with CAD impaired VEGF-induced angiogenesis via eNOS/Akt signaling pathway. Taken together, our findings suggest that oxidatively modified HDL from patients with CAD may be a contributing factor to reasons why therapeutic angiogenesis trials failed using VEGF recombinant protein or VEGF gene therapy.
Abstract 12451: Achievement of Weight Loss With Hypertension Control Among Adults With Incident Hypertension
Authors: Johnson Heather M , Bartels Christie M , Thorpe Carolyn T , Pandhi Nancy , Jacobs Elizabeth A , Smith Maureen A
Published: July 2021

Background:
Being overweight or obese independently contributes to the development of target organ damage among adults with hypertension. Weight loss and hypertension control are critical to reduce morbidity in this population. The purpose of this study is to evaluate rates and predictors of weight loss among adults with incident hypertension who achieve hypertension control.

Methods:
We conducted an analysis of overweight or obese ≥18 year-olds with incident hypertension receiving regular primary care in a large, academic group practice from 2008-2011. Patients with a previous hypertension diagnosis or antihypertensive prescription were excluded. Patients (n=4,913) were followed until hypertension control. Patients were classified by body mass index (BMI) at baseline as overweight or class I, II, or III obese. Weight was assessed at study entry and within 30 days of achieving hypertension control. Kaplan-Meier analysis estimated the probability of any weight loss (≥2.0 kg). Cox proportional-hazard models (HR; 95% CI) were fit to identify predictors of weight loss at the time of hypertension control.

Results:
Patients were followed a mean 12.4 (SD 10.3) months. Overall, 32% (n=1,567) had ≥2.0 kg weight loss at the time of hypertension control, almost half (n=718) lost ≥5.0 kg. Patients with lower BMI at study entry had lower weight loss rates at the time of hypertension control. Compared to class III obese (BMI ≥40 kg/m2), overweight patients had a 37% lower rate of losing >2.0 kg (HR: 0.63; 0.55-0.73), class I obese had 27% lower rates (HR: 0.73; 0.64-0.85) and class II obese had 16% lower rates (HR 0.84; 0.71-0.98). Middle-aged adults (40-59 years old) had 27% lower weight loss (HR 0.83; 0.73-0.94) compared to ≥60 year-olds. Females (HR: 0.90; 0.81-0.99), patients with higher health care utilization (HR 0.86; 0.75-0.99), and Stage 1 hypertension (HR: 0.87; 0.77-0.98) had lower weight loss rates. Socioeconomic and provider factors did not predict weight loss.

Conclusions:
Among overweight and obese patients that achieved hypertension control, only 32% had ≥2.0 kg weight loss and 15% achieved ≥5.0 kg weight loss. Effective weight loss interventions are needed to maintain hypertension control and decrease target organ damage in this population.
Abstract 12500: Attenuated Basal Left Ventricular Wall Contraction in Patients With Mitral Valve Prolapse Can be Secondary to Annular Dilatation With Augmented Closing Force: Pre- and Post-Operative Speckle Tracking Echocardiographic Study
Authors: Fukuda Shota , Song Jae-Kwan , Kuwaki Hiroshi , Jang Jeong-Yoon , Takeuchi Masaaki , Sun Byung-Joo , Kim Yun-Jeong , Iwataki Mai , Otani Kyoko , Eto Masataka , Yoshitani Hidetoshi , Tamura Masahito , Abe Haruhiko , Nishimura Yosuke , Levine Robert A , Otsuji Yutaka
Published: July 2021

Introduction:
Mitral annulus (MA) is generally enlarged in patients with mitral valve prolapse (MVP), which may raise MV closing force acting to shift the MV and its adjacent basal left ventricular (LV) wall toward left atrium.

Hypothesis:
MA dilatation with augmented MV closing force may disturb basal LV wall systolic contraction in patients with MVP.

Methods:
In 11 healthy controls and 34 patients with MVP, 3 apical views were obtained to assess longitudinal strain of basal- and mid-LV segments by speckle tracking analysis. The ratio of basal- to mid-LV strain value was then calculated. MA area was calculated by annulus diameters in apical 4- and 2- chamber views. MV closing force was calculated as MA area х (systolic blood pressure - 10).

Results:
Patients with MVP showed significantly larger MA area (5.3±1.0 vs 3.8±0.7 cm2/m2) and MV closing force (638±192 vs 431±66 mmHg•cm2/m2), and reduced basal-LV strain (-18±3 vs -21±2%) than controls (all p<0.005), whereas mid-LV strain was similar between the 2 groups (-22±4 vs -22±3%, p=0.4). Consequently, significantly lower basal/middle ratio was observed in patients with MVP compared to controls (0.86±0.11 vs 0.95±0.08, p=0.004). By multivariate analysis, reduced basal/middle strain ratio was associated with augmented MV closing force (β=0.45, p=0.005) (Figure A), independent from the severity of mitral regurgitation (p=0.7). The basal/middle strain ratio significantly increased to 1.07±0.10 after annular size reduction in 5 patients with surgical MV plasty (p=0.04) (Figures B and C).

Conclusions:
In patients with MVP, an increase in MV closing force corresponding to MA dilatation, as opposed to the severity of mitral regurgitation, was related to attenuated basal LV wall contraction, which can be restored by MV plasty with annular size reduction.
Abstract 12526: AKAP150-Mobilized PKC Activation Mediates Myocardial Dysfunction in Diabetes
Authors: Chao Zeng , Wang Jinyi , Li Na , Shen Mingzhi , Wang Haichang , Yu Qiujun
Published: July 2021

Background:
Chronic activation of conventional PKC (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cPKC signaling in cardiomyocytes. This study was aimed to investigate the role of AKAP150 in cPKC-mediated cardiac injury in diabetes.

Methods and Results:
In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose treated neonatal rat cardiomyocytes, expression of AKAP150 increased significantly at both mRNA and protein levels, with a marked elevation in expression and activity of cPKC and phosphorylation levels of p65NF-κB and p47phox. AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150 targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction, as evidenced by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose induced cardiomyocyte apoptosis (TUNEL staining and annexin V/PI flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity and lipid peroxidation). More importantly, reduced AKAP150 expression significantly reversed high-glucose induced membrane translocation and activation of cPKC, and inhibited phosphorylation of p65NF-κB and p47phox. Immunofluorescent co-expression and immunoprecipitation analysis indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane in both diabetic myocardium and high-glucose treated cardiomyocytes. Further studies using antibodies and specific inhibitors against different cPKC isoforms revealed that AKAP150 preferentially co-localized and functionally bound with PKC α and β, which are the major isoforms responsible for cardiac glucotoxicity.

Conclusions:
Cardiac AKAP150 positively responds to hyperglycemic stimuli and functions to enhance the efficiency of glucotoxicity signaling through a cPKC/p47phox/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis and oxidative stress.
Abstract 12529: Low Dose Oral Cyclophosphamide Therapy Reduces Atherosclerosis Progression and Promotes Plaque Stability in a Murine Model of Atherosclerosis
Authors: Sato-Okabayashi Yayoi , Nishida Chiemi , Hiroyuki Daida , Munakata Shinya , Shimazu Hiroshi , Heissig Beate , Hattori Koichi
Published: July 2021

Introduction:
Atherosclerosis is a chronic inflammatory disease and the primary cause of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions. Extended survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. The objective of this study was to examine the antiatherosclerotic effects of CPA and the underlying mechanism in a murine model of atherosclerosis.

Hypothesis:
CPA treatment can alter inflammatory processes pivotal for the development of atherosclerosis, therefore limiting disease progression.

Method:
Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet received CPA resuspended in drinking water (37.5 g/kg /day p.o.) or water for 12 weeks, respectively. In an interventional protocol, mice fed a high fat diet received the same dose of CPA or water from week 14 to 18, respectively. Mice were sacrificed at week 12, 14 and 18, and aorta, peripheral blood cells, spleen cells and peritoneal cells of treated mice were analysed using histological methods and FACS analysis.

Result:
In a preventive protocol, continuous oral administration of low-dose CPA prevented disease initiation in ApoE-/- mice fed with a high fat diet. Encouraged by these data we treated mice with pre-established atherosclerosis for 4 weeks with CPA, in an interventional protocol. CPA treatment delayed disease progression in mice with advanced atherosclerosis and reduced the macrophage infiltration in plaques. Importantly, improved plaque stability with a thicker fibrous cap, and an increase in collagen deposition and decreased matrix metalloproteinase-2 and -9 expression, and a reduction of classical inflammatory macrophage (M1) numbers was observed. In addition, CPA treatment reduced the numbers of IFN-γ-producing TH1, but not TH2 lymphocytes in vivo.

Conclution:
Our data demonstrate that oral treatment with CPA inhibits atherosclerosis initiation and progression in ApoE-/- mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, CPA may be a valuable drug for treating advanced atherosclerosis.