bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12153: Impact of a Hybrid Nurse-Led Intervention for the Prevention of Progressive Cardiac Dysfunction in High Risk Individuals: Results From a Pragmatic, Randomized Trial (the NIL-CHF Study)
Authors: Stewart Simon , Carrington Melinda , Chan Yih Kai , Jennings Garry , Wong Chiew ,   NIL-CHF Investigators
Published: July 2021

Background:
The natural history of chronic heart failure (CHF) is characterized by initial cardiac insult and/or stressors over time that leaves affected individuals at high risk for progressive cardiac dysfunction and eventual development of the syndrome.

Methods:
Of a total of 624 subjects at high risk of developing CHF randomized into the NIL-CHF Study comparing a hybrid program of home and clinic-based follow-up (NIL-CHF group) to Standard Care, 454 (73%) underwent serial echocardiography at 1 month post index cardiac hospitalization and at 3 years. At both time points (nil signs/symptoms of CHF at baseline), these were blindly classified as follows: 1) no cardiac abnormality, 2) systolic dysfunction/HFrEF - LVEF ≤ 45% ), 3) diastolic dysfunction/HFpEF as defined by any moderate diastolic dysfunction (with pseudonormalization pattern) or E/E prime ratio ≥ 15, 4) combination of 2 & 3 and 5) other cardiac abnormality (including LVH). Pre-specified criteria were used to determine - i) no change, ii) improvement or iii) deterioration in cardiac function from baseline to 3 years.

Results:
Mean age was 66±11 years, 71% were male, 70% were hospitalized with an acute coronary syndrome and 62% and 26%, respectively, were being treated for hypertension and diabetes. At baseline 25.2% vs. 28.4% (p=ns), 15.1% vs. 9.1% (p<0.05), 35.1% vs. 32.4% (p=ns) and 34.3% vs. 39.6% had normal cardiac function, HFrEF, HFpEF (13% both HFrEF and HFpEF overall) and LVH (the predominant “other” cardiac abnormality), respectively. At 3 years the proportion of subjects with reversal of pre-existing HFrEF or HFpEF was lower in the NIL-CHF group (23% vs. 16%; p=0.063). Moreover, significantly more NIL-CHF subjects demonstrated any form of cardiac recovery/reversal on echocardiography (39% vs. 25%, p=0.011, 95% CI 1.35, 95% CI 1.04, 1.76). They also demonstrated significantly greater regression to normal LV structure (36% vs. 25%; p=0.047) among those with LVH at baseline.

Conclusions:
These pre-specified analyses (secondary endpoint) of the recently completed NIL-CHF Study suggests a cardio-protective effect conferred by a long-term, nurse-led, home and clinic-based intervention targeting hospitalized individuals at high risk for developing CHF.
Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice
Authors: Chen Weiqin , Zhou Hongyi , Saha Pradip , Li Luge , Chan Lawrence
Published: July 2021

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.
Abstract 12200: Comparison of Exercise-Induced Hemodynamic Changes Between Anterior and Posterior Mitral Prolapse in Patients With Asymptomatic Degenerative Mitral Regurgitation
Authors: Yi Jeong-Eun , Jung Hae-Ok , Youn Ho-Joong
Published: July 2021

Background:
Exercise-induced hemodynamic changes depending on the location of prolapsed leaflet have not been elucidated. The study tried to compare exercise-induced hemodynamic changes between AML and PML prolapse in asymptomatic degenerative MR.

Methods:
We enrolled 29 patients with asymptomatic moderate to severe degenerative MR (i.e., mitral valve prolapse or flail) and patients were classified by the location of prolapsed leaflet including 15 with anterior mitral leaflet [AML] and 14 with posterior mitral leaflet [PML]. Resting and semi-supine bicycle exercise Doppler-echocardiography were performed and MR was quantified at rest and exercise with effective regurgitant orifice area (EROA) and regurgitant volume calculated with the proximal isovelocity surface area (PISA) and the quantitative Doppler methods. Exercise-induced PHTN was defined as a right ventricular systolic pressure (RVSP) > 60 mmHg during exercise.

Results:
At rest, baseline echocardiographic parameters were not different between the two groups. During exercise, mean EROA and regurgitant volume (RV) were markedly increased in patients with PML prolapse compared to those with AML prolapse (ΔEROA, 0.21±0.19 vs 0.05±0.10, P=0.012 and ΔRV 19.4±20.0 vs 3.3±17.5, P=0.030). Moreover, exercise-induced change of RVSP was more significant in PML prolapsed compared with AML prolapsed (ΔRVSP, 42.2±10.5 vs 26.7±8.6, P<0.0001). However, the prevalence of exercise-induced PHTN during the exercise was similar in both groups. Interestingly, PML prolapsed demonstrated more increase in LV cavity volume and LV spherical change during exercise compared with AML prolapse as shown in table 1.

Conclusion:
During exercise, PML prolapsed is associated with more increase of MR severity, more increased RVSP, and more significant LV remodeling compared to the AML prolapsed in patients with moderate to severe degenerative MR.
Abstract 12291: Contribution of Rare Mutations in Mendelian Hypercholesterolemia Genes to Risk for Premature Coronary Artery Disease in the Population
Authors: Won Hong-Hee , Do Ron ,   on behalf of the Myocardial Infarction Genetics Sequencing Consortium
Published: July 2021

Introduction:
Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for coronary artery disease (CAD). Rare mutations in at least 6 genes lead to Mendelian forms of high or reduced LDL-C; three (
APOB, LDLR, PCSK9
) act in a dominant pattern whereas three (
ABCG5, ABCG8, LDLRAP1
) in a recessive pattern. We address to what extent rare mutations in Mendelian LDL-C genes contribute to early CAD risk in the population.

Methods:
We sequenced the exons of the 6 genes in 9,329 early CAD cases (myocardial infarction, angiographic CAD, or coronary revascularization in men≤50 and women≤60) and 10,245 controls from 9 studies using targeted and whole exome next-generation sequencing. We tested 3 sets: ‘Null alleles’ (nonsense, splice-site, or frameshift); ‘Deleterious (7/7)’ (null and missense annotated as damaging by 7 algorithms); and ‘Deleterious (6/7)’ (null and missense annotated as damaging by at least 6 algorithms). Given the rarity of deleterious mutations, we aggregated these mutations in each gene and tested for an excess or deficit in cases
vs
. controls.

Results:
Counts of mutations are provided in Table. Null mutations in
LDLR
, carried by 1:500 participants, confered a 8-fold increase in CAD risk (P=8х10
-7
) whereas heterozygosity for a null mutation in
ABCG5
(1:650 frequency) was associated with a 3-fold increased risk (P=5х10
-3
). ‘Deleterious (7/7)’ mutations in
LDLR
, carried by 1:100 participants, confered a 4-fold increased risk (P=8х10
-17
) whereas heterozygosity for a ‘Deleterious (7/7)’ mutation in
ABCG5
(1:250 frequency) was associated with a 2-fold increased risk (P=2х10
-3
). Heterozygous null allele carriers at
LDLR
and
ABCG5
had increased LDL-C (P<0.001).

Conclusions:
Of early CAD cases, 2-3% carry a rare, deleterious mutation at
LDLR
or
ABCG5
associated with increased risk. Although previously reported to cause recessive sitosterolemia, we find that heterozygosity for a null allele at
ABCG5
is associated with markedly higher early CAD risk.
Abstract 12320: Assessment of Post-Procedural Aortic Regurgitation After Transcatheter Aortic Valve Replacement During the Procedure: An Intraprocedural Transesophageal Echocardiography Study
Authors: Mihara Hirotsugu , Shibayama Kentaro , Jilaihawi Hasan , Itabashi Yuji , Berdejo Javier , Utsunomiya Hiroto , Siegel Robert J , Makkar Raj R , Shiota Takahiro
Published: July 2021

Introduction:
The assessment of post-procedual aortic regurgitation (PAR) after transcatheter aortic valve replacement (TAVR) has not been validated. The purpose of this study was (1) to investigate the value of holodiastolic flow reversal (HDFR) in the descending aorta in patients with PAR after TAVR and (2) to determine which color Doppler parameters are useful for PAR grading using the intraprocedural transesophageal echocardiography (iTEE).

Hypothesis:
We hypothesized that HDFR in the descending aorta and any color Doppler parameters can delineate significant PAR after TAVR.

Methods:
Three hundred-eighty patients with severe aortic stenosis underwent TAVR with the Edwards SAPIEN valve with 131 pulsed-wave Doppler tracings from the descending aorta had assessed by iTEE. PAR was evaluated using 2D color Doppler by the cross-sectional area of the vena contracta (VCA) at the aortic annular plane, and by the longitudinal jet extent (mosaic signals, Figure A) compared to the location of the tip of the anterior mitral leaflet (AML). Significant PAR was defined as VCA of ≥10 mm2, corresponding to greater than a moderate grade.

Results:
In patients with any grade of PAR, pulsed-wave Doppler tracing from the descending aorta, jet extent and VCA were obtained in 100%, 80%, and 74%, respectively. All patients with consistent HDFR had significant PAR. By multivariate analysis, a consistent HDFR and jet extent beyond the tip of AML were independent predictors of significant PAR. A consistent HDFR and jet extent beyond the tip of AML predicted significant PAR with specificity of 100% and 97%, respectively. In the other hand, patients with both negative HDFR and jet extent of less than halfway to the tip of AML had no significant PAR with a 97% specificity.

Conclusions:
The presence of HDFR with each cardiac cycle and jet extent beyond the tip of AML are indicative of significant PAR.
Abstract 12357: Enzyme Kinetic Model Reveals Novel Characteristics of Pharmacodynamic Interaction of NSAIDs and Aspirin at COX-1, Which Lead to High on Aspirin Platelet Reactivity (HAPR)
Authors: Bagheri Saghar , Hafner Dieter , Hohlfeld Thomas
Published: July 2021

Introduction:
Non-aspirin NSAIDs attenuate the antiplatelet action of aspirin leading to High on Aspirin Platelet Reactivity (HAPR). However, detailed features of this interaction are still unresolved. Both competitive as well as non-competitive interaction at the cyclooxygenase-1 (COX-1) enzyme have been proposed.

Hypothesis:
We examined whether competitive enzyme kinetics describe COX-1 inhibition by aspirin and HAPR and if they are compatible with results obtained experimentally.

Methods:
We have developed an enzyme kinetic model of the aspirin/NSAID interaction at COX-1 using mathematical modelling and have varied enzyme kinetic parameters to predict the occurrence and the extent of HAPR. Subsequently, the predictions obtained were experimentally verified with selected NSAIDs using light transmission aggregometry and immunoassay for platelet thromboxane (TX) synthesis.

Results:
Enzyme kinetic modelling predicted that only low- and medium-affinity NSAIDs (Ki ≥1 μM), but not high-affinity NSAIDs, interfere with COX-1 inhibition by aspirin. Furthermore, the interaction was predicted to be most extensive at high concentrations of arachidonic acid (1mM). Experimental results confirmed the model by showing that low or medium-affinity COX-1 inhibitors piroxicam, dipyrone and celecoxib (each n=5-10) largely prevented the inhibition of aggregation and platelet TX synthesis in vitro by 30 μmol/L aspirin whereas the high-affinity COX-1 inhibitor SC560 (n=6) did not interfere with aspirin at all. In accordance to the mathematical model, aspirin/NSAID interaction was more pronounced in presence of high (1mmol/L) versus low (0.3mmol/L) concentration of arachidonic acid. Hence, the kinetic model was validated experimentally.

Conclusion:
Both enzyme kinetic modelling and experimental results suggest competitive antagonism of NSAID and aspirin at COX-1 as a cause for HAPR, possibly resulting in cardiovascular events. Critical parameters that influence this interaction are drug concentrations and NSAID affinity. Interestingly, the concentration of arachidonic acid also influences the NSAID/aspirin interaction, suggesting that “fatty acid tone” and lipid metabolism may influence this unfavourable drug/drug interaction.
Abstract 12437: Prediction of Mitral Regurgitation Progression With Advanced Ischemic Cardiomyopathy - A Multi-Modality Study
Authors: Kusunose Kenya , Obuchowski Nancy , Cavalcante Joao , Tsutsui Rayji S , Popovic Zoran B , Thomas James D , Desai Milind Y , Flamm Scott D , Griffin Brian P , Kwon Deborah H
Published: July 2021

Introduction:
Ischemic mitral regurgitation (IMR) is associated with poor outcomes. Determining risk for the presence and progression of IMR may be critical for risk stratification.

Hypothesis:
We hypothesize that a multi-modality approach can evaluate the progression of IMR in patients with advanced ischemic cardiomyopathy (ICM) and create a risk model for the prediction of IMR progression.

Methods:
Consecutive ICM patients who underwent cardiac magnetic resonance (CMR) and echocardiograms at baseline with echocardiographic follow-up were included. CMR was used to assess global and regional left ventricular (LV) remodeling, myocardial scarring, and mitral valve geometry. The effective regurgitant orifice area (EROA) was calculated from the proximal isovelocity surface area by echocardiography. We identified the best performing model for prediction of worsening IMR based on the c-index.

Results:
We evaluated 693 patients (age 62±11). The following factors were independently predictive of an increased EROA at baseline (n=693): higher total scar% (p=0.002) and higher ESVi (p<0.001). In regards to progression of IMR over time, the following variables were independently predictive (n=481): older age (p=0.015), lower GFR (p<0.001), higher EROA at baseline (p<0.001), lower tenting area (p=0.008), higher ESVi (p=0.001), and the interaction of total scar % and treatment type (medical vs revascularization vs valve surgery, Figure) (p=0.001). The c-index for worsened IMR prediction for the ICM was 0.730 from our training sample (n=164).

Conclusions:
The variables which predict IMR at baseline and progression of IMR over time slightly differ. Higher total scar% and higher ESVi are independently associated with increasing IMR at baseline. However, higher EROA at baseline, lower tenting area, higher ESVi and total scar% * treatment type were associated with progression of IMR over time. The risk model of IMR progression was moderately predictive in this cohort.
Abstract 12559: Rapid Atrial Pacing Augments Fibrinogen Expression With Activation of IL-6/STAT3 Signaling Pathway in the Rat Liver
Authors: Yaegashi Takanori , Kato Takeshi , Usui Soichiro , Kanamori Naomi , Furusho Hiroshi , Ootsuji Hiroshi , Takashima Shinichiro , Murai Hisayoshi , Kaneko Shuichi , Takamura Masayuki
Published: July 2021

Introduction:
Atrial fibrillation (AF) activates coagulation system leading to hypercoagulation of the blood. However, it is still unknown whether rapid atrial excitation per se affects gene expression remotely in the liver, the major source of coagulation factors and other prothrombotic molecules.

Methods and Results:
The AF model was created by rapid atrial pacing at the frequency of 1200 bpm in anesthetized 10-week-old Sprague-Dawley rats. The livers and peripheral blood cells were collected and analyzed after the pacing of 12 hours. Sham-operated rats underwent the identical procedure without electrical stimulation. DNA microarray revealed marked changes in hepatic gene expression after 12 hours atrial pacing. Hierarchical clustering with 13871 filtered genes or genes related to coagulation including fibrinogen, demonstrated clusters for the pacing or sham. The quantitative RT-PCR focused on prothrombotic molecules revealed that rapid atrial pacing significantly augmented the hepatic mRNA expressions of fibrinogen α, β, γ-chain, prothrombin, antithrombin-III, plasminogen, and coagulation factor X. The increase of fibrinogen protein in the liver was also confirmed by Western blotting (Figure A). We further investigated the mechanism of enhanced fibrinogen production and identified increased IL-6 mRNA expression in the peripheral blood cells by rapid atrial pacing (Figure B). IL-6 was also prominent in CD11b positive cells infiltrated in the liver, and possibly promoted STAT3 phosphorylation in the nuclei of hepatocytes (Figure C).

Conclusions:
The rapid atrial excitation mimicking paroxysmal AF altered the hepatic gene expressions of prothrombotic molecules. Increased fibrinogen expression in the liver was accompanied by activation of IL-6/STAT3 signaling pathway in the peripheral blood and the liver. These findings might imply the cardio-hepatic interaction in AF and provide new insight into the prevention of AF-related thromboembolism.
Abstract 12571: Successful Catheter Ablation of Ventricular Tachycardia is Associated With Reduction of Mortality in Patients With Ventricular Tachycardia and Nonischemic Dilated Cardiomyopathy
Authors: Dinov Borislav , Arya Arash , Schirripa Valentina , Bertagnolli Livio , Fiedler Lukas , Bollmann Andreas , Rolf Sascha , Piorkowski Christopher , Hindricks Gerhard
Published: July 2021

Introduction:
Recent publications reported on higher recurrence rates and lack of survival benefit after catheter ablation (CA) of ventricular tachycardia (VT) in nonischemic dilated cardiomyopathy (NIDCM).

Methods:
We aimed to investigate the VT recurrence and cardiac mortality in patients with NIDCM ablated for VT. The studied cohort was divided in 2 groups depending on procedure success: complete success (group 1), and failure or incomplete success (group 2). Success definition was based on the VT inducibility after CA. The patients were prospectively followed for cardiac mortality and VT recurrence.

Results:
104 patients with NIDCM (87 males, mean age 59.65 ± 14.69 years, mean ejection fraction 33.42 ± 11.42 %) underwent VT ablation. Ventricular stimulation after CA was not attempted in 13 (12.5%) patients. Out of the rest 91, complete success was achieved in 62 (68.1%) patients (group1), and incomplete success or failure in 29 (31.9%) patients (group 2). During 2-years follow-up, VT recurrence was observed in 56.5% in group 1 vs. 82.8% in group 2. Incomplete success was associated with higher VT recurrence (HR 1.91; 95% CI 1.13-3.22; p=0.015). The 2-years mortality was 14.5% in group 1 vs 34.5% in group 2. The probability for death was 3-times higher in group 2 (adjusted HR 3.18; 95% CI 1.18-8.56; p=0.022). The primary and secondary endpoints were comparable between patients with idiopathic, post-myocarditis and secondary NIDCM.

Conclusion:
Procedure success, defined as complete VT noninducibility after CA of VT, was associated with reduced VT recurrence and improved survival in patients with nonischemic dilated cardiomyopathy.
Abstract 12591: Impact of Aldosterone Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism
Authors: Matsumoto Takeshi , Higashi Yukihito ,   Div of Regeneration and Medicine, Hiroshima Univ Hosp, Oda Nozomu , Iwamoto Akimichi , Iwamoto Yumiko , Kajikawa Masato , Maruhashi Tatsuya , Nakashima Ayumu , Noma Kensuke ,   Div of Regeneration and Medicine, Hiroshima Univ Hosp, Kihara Yasuki
Published: July 2021

Background:
Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs) activity. Primary aldosteronism (PA) is a most common cause of secondary hypertension. Recent studies have shown that risk of cardiovascular events is higher in patients with PA than in patients with essential hypertension (EH). However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA.

Methods:
Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone producing adenoma (APA) group (50.7±14.3 years, 9 males), 23 patients with idiopathic hyperaldosteronism (IHA) group (55.8±9.9 years, 12 males), and 33 age-, gender-, and blood pressure-matched EH group (54.9 ± 10.7 years, 18 males).

Results:
FMD was significantly lower in the APA group than in the IHA group and EH group (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P<0.05, respectively), whereas there was no significant difference in FMD between the IHA group and EH group. There was no significant difference in the response of nitroglycerine in three groups. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P<0.05 and P<0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. FMD correlated with age (r=-0.31, P<0.01), brachial arterial diameter (r=-0.44, P<0.01), plasma aldosterone concentration (PAC) (r=-0.35, P<0.01) and plasma renin activity ratio (ARR) (r=-0.34, P<0.01). ROCK activity correlated with age (r=-0.24, P=0.04), PAC (r=0.33, P<0.01) and ARR (r=0.46, P<0.01).

Conclusions:
APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.
Abstract 12606: Autophagy is Required for Mitochondrial Biogenesis in the Heart
Authors: Li Zhonggang , Zhang Quanjiang , Pires Karla , Abel E. Dale
Published: July 2021

Autophagy is an essential process that maintains cellular homeostasis via lysosomal degradation pathways. Autophagy has been found to be involved in various pathophysiological conditions in the heart, including myocardial hypertrophy and ischemic heart disease. However, the precise mechanism by which autophagy maintains cardiac function in the non-stressed heart is incompletely understood. We generated cardiac-specific ATG3 deficient mice (cATG3 KO mice) by crossing αMHC-Cre mice with floxed ATG3 mice. Relative to their wild type (WT) littermates, cATG3 KO mice revealed reduced ATG3 expression and inhibited autophagy specifically in the heart. At 4 months of age, cATG3 KO mice showed impaired cardiac contractile function, characterized by a 25% reduction in fractional shortening by echocardiography (p <0.01), Moreover, cATG3 KO mice revealed increased lipid accumulation, reduced fatty acid oxidation and impaired mitochondrial respirations in the heart, without evidence of fibrosis or inflammation. Mitochondrial dysfunction in cATG3 KO mice was accompanied with mitochondrial content loss and reduced expression of mitochondrial biogenesis related genes (PGC1α, NRF1, NRF2 and TFAM). Interestingly, autophagy inhibition, induced mitochondrial biogenesis defects and mitochondrial dysfunction in neonatal cATG3 KO mice (1 week old), prior to the onset of cardiac contractile dysfunction and heart failure, suggesting that cardiac mitochondrial dysfunction may be an early event in the progression of heart failure in the autophagy deficient mice. Finally, in response to exercise training mitochondrial biogenesis (PGC1 alpha induction and increased respiration rates) was completely inhibited in ATG3 deficient mice. In conclusion, autophagy is essential for generating signals that promote mitochondrial biogenesis, and is indispensable for normal heart function under basal conditions.
Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis
Authors: Wang Xiaohong , Qin Dongze , Essandoh Kobina , Huang Wei , Yang Liwang , Gu Haitao , Millard Ronald W , Wang Yigang , Fan Guo-Chang
Published: July 2021

Introduction:
Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored.

Methods and Results:
C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p<0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p<0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: ﬂ]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p<0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h).

Conclusions:
Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.
Abstract 12637: Utility of the Wearable Cardioverter-Defibrillator for Patients With Newly Diagnosed Non-Ischemic Cardiomyopathy?
Authors: Singh Madhurmeet , Alluri Krishna , Voigt Andrew , Wang Norman , Jain Sandeep , Mendenhall George , Barrington William , Nemec Jan , Saba Samir , Adelstein Evan
Published: July 2021

Introduction:
The wearable cardioverter-defibrillator (WCD) is approved for prevention of sudden cardiac death in patients with newly diagnosed cardiomyopathy and LVEF < 35% who do not yet meet criteria for implantation of an implantable cardioverter-defibrillator (ICD). While there are some data supporting WCD use in patients with ischemic cardiomyopathy (ICM), data in patients with nonischemic cardiomyopathy (NICM) are lacking.

Methods:
This was a retrospective review of outcomes for all NICM patients prescribed a WCD at a large tertiary academic center from 6/2004 - 1/2014 for a newly diagnosed cardiomyopathy and no prior sustained ventricular arrhythmia. During this time period, 454 patients were prescribed a WCD, of whom we excluded 161 patients with ICM.

Results:
The 183 (40%) patients with NICM consisted of 70% men, aged 57 +/- 15 years old, with mean EF 23% +/- 8% and LV end-diastolic dimension 4.5 +/- 2.8 cm. DM and HTN were prevalent (20% and 51%, respectively). At NICM diagnosis, 21% had LBBB and 36% had known history of AF. Patients wore the WCD for 13,124 patient-days, each averaging 72 +/- 55 days and with fairly high compliance (18.3 +/- 5.7 hours/day). Medication use consisted of 90% beta-blockers, 88% ACE inhibitors, 85% diuretics, 16% digoxin, and 17% anti-arrhythmic drugs. NSVT was documented in 42% of patients prior to WCD prescription. During follow-up, 60 (33%) patients improved LVEF to > 35%, obviating an indication for ICD implantation, whereas 79 (43%) patients received an ICD. The remainder died (n=17), were lost to follow-up (n=20), refused ICD implant (n=5), or are still wearing the WCD (n=2). No appropriate WCD shocks were delivered in any NICM patient, yet 3 inappropriate shocks were delivered (1.6%). Based on estimated rental costs provided by the manufacturer, the total cost of WCD use in this population was $1,449,360.

Conclusions:
In this large, tertiary care center registry of patients with newly recognized NICM, no patient received an appropriate shock from the WCD whereas several inappropriate shocks were delivered, despite nearly one-half of patients having documented significant ventricular ectopy. Given the significant expense and inconvenience of the WCD, its use in this population requires prospective study.
Abstract 12694: The Mechanistic Link Between Interatrial Adiposity, Morphological Left Atrial Remodeling and Functional Features in Asymptomatic Population
Authors: Lai Yau-Huei , Yun Chun-Ho , Kuo Jen-Yuan , Hou Jia-Yin , Yeh Hung-I , Hung Chung-Lieh
Published: July 2021

Introduction:
Left atrial (LA) mechanics play a key role in heart failure (HF) development and atrial fibrillation. So far, the pericardial adipose tissue had been shown to exert local effects on adjacent cardiac structures. However, the precise mechanisms between regional fat and LA remodeling in asymptomatic population remains largely unexplored.

Hypothesis:
We hypothesize that LA function is negatively affected by pericardial fat burden.

Methods:
We studied 361 consecutive subjects (age: 51.8+/- 8.8, 31% female) free from significant valvular disorders, atrial fibrillation and clinical HF. Regional visceral adiposity including total pericardial fat (PCF) and thoracic periaortic fat (TPAF) volumes, interatrial septum (IAS) and left atrioventricular groove (AVG) fat thickness were all obtained by multidetector computed tomography (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). LA volumes, contractile performance and reservoir function as well as conduit capacity were all measured by echocardiography.

Results:
All four adiposity measures (PCF, TPAF, AVG and IAS) were associated with larger LA volume indices (all p<0.05). Furthermore, IAS and AVG were related to larger LA kinetic energy and worse reservoir capacity (both p<0.05). In multivariate models, IAS fat thickness remained independently associated with increased LA conduit function (β-coef: 0.28), ejection force (β-coef: 0.15) and impaired LA reservoir function (β-coef: -0.20, all p<0.05), even after adjusting for clinical variables.

Conclusions:
Accumulated visceral adiposity, especially interatrial fat depots, may be partially associated with LA structural and functional remodeling, which is characterized by impaired LA reservoir capacity, augmented contractile and conduit performance. Our data suggested that compensatory LA mechanistic adaptation with greater visceral fat burden may exist in asymptomatic population.
Abstract 12769: Amplitude-Spectral Area of the Ventricular Fibrillation Waveform and Chest Compression Quality in Witnessed and Unwitnessed Out-Of-Hospital Cardiac Arrest: Can We Predict Who is Unlikely to Survive?
Authors: Indik Julia , Conover Zacherie , McGovern Meghan , Silver Annemarie , Spaite Daniel , Bobrow Bentley , Kern Karl
Published: July 2021

Background:
Previous investigations in human out of hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) have shown that the frequency-based waveform characteristic, amplitude spectral area (AMSA) predicts defibrillation success and is associated with survival to hospital discharge. We evaluated the relative strength of factors associated with hospital discharge including witnessed/unwitnessed status, chest compression (CC) quality and AMSA. We then investigated if there is a threshold value for AMSA that can identify patients who are unlikely to survive.

Methods:
Adult OHCA patients (age ≥18), with initial rhythm of VF from an Utstein-Style database (collected from 2 EMS systems) were analyzed. AMSA was measured from the waveform immediately prior to each shock, and averaged for each individual subject (AMSA-ave). Univariate and stepwise multivariable logistic regression, and receiver-operator-characteristic (ROC) analyses were performed. Factors analyzed: age, sex, witnessed status, time from dispatch to monitor/defibrillator application, number of shocks, mean CC rate, depth, and release velocity (RV).

Results:
140 subjects were analyzed, [104 M (74%), age 62 ± 14 yrs, witnessed 65%]. Survival was 38% in witnessed and 16% in unwitnessed arrest. In univariate analyses, age (P=0.001), witnessed status (P=0.009), AMSA-ave (P<0.001), mean CC depth (P=0.025), and RV (P< 0.001) were associated with survival. Stepwise logistic regression identified AMSA-ave (P<0.001), RV (P=0.001) and age (P=0.018) as independently associated with survival. The area under the curve (ROC analysis) was 0.849. The probability of survival was < 5% in witnessed arrest for AMSA-ave < 5 mV-Hz, and in unwitnessed arrest for AMSA-ave < 15 mV-Hz.

Conclusion:
In OHCA with an initial rhythm of VF, AMSA-ave and CC RV are highly associated with survival. Further study is needed to evaluate whether AMSA-ave may be useful to identify patients highly unlikely to survive.
Abstract 12792: Relationship Between Depression and Brain Injury in Heart Failure
Authors: Shinnick Mary Ann , Woo Mary A , Kumar Rajesh
Published: July 2021

Introduction:
Depression is common in heart failure (HF), and is an independent predictor of mortality and morbidity. MRI detected brain injury in many regions, including those associated with depressive symptoms (hippocampus, insular lobes). However, the association between depressive symptoms and documented brain injury has not been reported in HF.

Methods:
Using a 3.0-Tesla MRI scanner, we assessed brain tissue injury (DTI-based mean diffusivity [MD] procedures [damage indicated by increased diffusion/MD value]) and depressive symptoms (Beck Depression Inventory-II [BDI]; BDI scores >17 indicate depression) in 16 HF (age 55.1 + 7.7 years; 12 males; LVEF 27.8 + 6.8) and 26 controls (age 49.7 + 10.8 years; 17 males). All HF subjects were NYHA Class I-II and were able to lie flat in an MRI scanner. Statistics consisted of Mann-Whitney U and Spearman’s Rho with significance set at p<0.05.

Results:
No significant differences were found between the groups for age or BMI. A significant difference in depression scores were seen between the groups on the BDI (HF = 10.75 + 7.66; controls= 3.54 + 4.33; p < 0.01) with only HF subjects exhibiting severe depression. Significant, positive correlations between brain injury and depression were detected in the right hippocampus, left insula, right frontal and right and left cerebellar areas (see Table 1).

Discussion:
This study reinforces the findings of depressive symptoms in HF patients but is the first study to show evidence of a correlation between damage to areas of emotion, cognition, and motor coordination in the brain and symptoms of depression. This study reveals a strong relationship between depression and brain damage in HF. Clinicians should not assume depression in HF is situational but may be due to brain injury.
Abstract 12824: Comparison of Tissue Doppler-Derived and Speckle Tracking-Derived Parameters for the Estimation of Left Ventricular Filling Pressure: A Multicenter Study in Japan
Authors: Hayashi Taichi , Yamada Satoshi , Nakabachi Masahiro , Iwano Hiroyuki , Sakakibara Mamoru , Okada Kazunori , Murai Daisuke , Nishino Hisao , Kusunose Kenya , Watanabe Kiyotaka , Ishizu Tomoko , Wakami Kazuaki , Yamada Hirotsugu , Dohi Kaoru , Seo Yoshihiro , Ohte Nobuyuki , Mikami Taisei , Tsutsui Hiroyuki
Published: July 2021

Background:
We conducted a multicenter study in Japan to compare tissue Doppler echocardiography-derived and speckle tracking echocardiography (STE)-derived parameters of left ventricular (LV) diastolic function for the estimation of LV filling pressure.

Methods:
Seventy-eight patients (age 59±14 years, 59 male) with structural heart diseases including angina pectoris (n=34), old myocardial infarction (n=15), dilated cardiomyopathy (n=13), hypertrophic cardiomyopathy (n=8), and hypertensive heart disease (n=8) were studied according to the same protocol in 5 university hospitals in Japan. LV mean diastolic pressure (MDP) was measured by using a micromanometer-tipped catheter. Early-diastolic mitral annular velocity (e′) was measured at septal and lateral side of the annulus and averaged, and the ratio of early-diastolic transmitral velocity to e′ (E/e′) was calculated. Global longitudinal strain was measured using STE in 3 apical views and averaged on a frame-by-frame basis to construct a time-strain curve as well as a time-strain rate (SR) curve. Then, the absolute value of peak longitudinal strain (LS), early-diastolic peak SR (LSR
E
), and that during isovolumic relaxation (IVR) period (LSR
IVR
) were measured. Similarly, peak circumferential strain (CS), early-diastolic peak circumferential SR (CSR
E
), and that during IVR (CSR
IVR
) were measured from 3 short-axis views.

Results:
E/e′ weakly correlated with MDP (r=0.50, p<0.001). E/LSR
IVR
and E/CSR
IVR
did not correlate with MDP, whereas there was a significant but weak correlation between E/LSR
E
and MDP (r=0.50, p<0.001) or between E/CSR
E
and MDP (r=0.41, p<0.001). In contrast, there was a good correlation between E/LS and MDP (r=0.70, p<0.001) or between E/CS and MDP (r=0.62, p<0.001). Especially, the correlation between E/LS and MDP was statistically better than that between E/e′ and MDP (p<0.01).

Conclusions:
STE-derived longitudinal parameters better correlated with MDP than circumferential parameters. Especially, E/LS was better than E/e′ for estimating LV filling pressure.
Abstract 12852: The Incremental Value of Three-Dimensional Transesophageal Echocardiography for the Diagnostic Assessment of Infective Endocarditis
Authors: Chirillo Fabio , Possamai Marta , Rugolotto Matteo , Martire Paola , Minniti Giuseppe , Giacomelli Sara , Scotton Piergiorgio , Polesel Elvio , Olivari Zoran
Published: July 2021

Two-dimensional transesophageal echocardiography (2D TEE) may fail to detect signs of infective endocarditis (IE) or to delineate complex anatomic lesions due to suboptimal visualization of the infected area. Three-dimensional (3D) TEE may have additional value; however, data are scarce. In 124 consecutive patients (85 M; Mean age 63 ± 14 years) with definite IE involving the aortic (36), mitral (35), tricuspid (5), ≤ 1 valve (6), and prosthetic valves (30),or pace-maker/ICD leads (12) the comparative analysis between 2D and 3D imaging focused on: 1) Presence and maximal dimension of vegetations; 2) Prediction of embolic events; 3) Location and dimension of valve perforation; 3) Prediction of successful mitral valve repair; 4) Identification and morphologic assessment of perivalvular complications.3D TEE detected more vegetations per patient (1.9 ± 2.1 vs 1.7± 1.6; p= 0.06), but this difference was significant only for vegetations on prosthetic valves and PM/ICD leads (2.2 ± 1.7 vs 1.1 ± 1.5; p=0.03). TomTec Software was used to crop the 3D volume to obtain the largest value for vegetations and perforation area. The 3D TEE maximal vegetation dimension was larger with a mean difference of 2.9 mm (95% CI, 1.9-4.52 mm) vs 2DTEE. The best cut-off value for prediction of embolic events was ≥18 mm with 3D TEE and ≥14 mm with 2D TEE. The positive predictive value for 3D TEE was not statistically higher (58% vs 52%). Valve perforation was identified in 10/19 patients with 2D TEE and in 18/19 patients with 3D TEE (p< 0.007) with subsequent surgical confirmation. Successful mitral valve repair was associated with a distance of the perforation > 3 mm from the leaflet tip and from commisures. This information was provided only by 3D TEE. Finally, 2D TEE missed 2/20 peri-annular extensions. After addition of 3D TEE all peri-annular extensions (20/20) were detected, without adding false positives.In 5 patients contrast 3D TEE provided visualization of the full extent of the defect and its precise anatomical location, prior to successful surgical resection. In conclusion 3D TEE is a feasible technique for the analysis of vegetation size and complex cardiac lesions caused by IE that may overcome the limitations of 2D TEE, providing incremental information useful for surgery
Abstract 12863: Non-Cardiac Chest Pain: Is It Really?
Authors: Boniface Nicholas , Kley Julian , Lisko John , Mikolich Brandon , Mikolich J Ronald
Published: July 2021

Background:
Of patients with acute chest pain(CP), only 10% have acute coronary syndrome. About 20% of these CP patients have an obvious non-cardiac etiology, while the remaining 70% undergo diagnostic testing to exclude coronary atherosclerosis(CAD). Myocardial perfusion imaging(MPI) is commonly used to assess these patients. A normal MPI effectively excludes CAD and the patient is labeled as having “non-cardiac” CP. Late gadolinium enhancement(LGE) by Cardiac MRI(CMR) offers detection of pericardial disease. This study was undertaken to assess the role of CMR in CP patients with a normal MPI.

Methods:
An institutional cardiac imaging database was queried for all patients with new onset CP. The study was composed of those CP patients who did not have ACS or an obvious non-cardiac etiology. The cohort was divided into 2 groups. Group A patients underwent MPI as their initial test and were negative for ischemia, but had continued CP. Group B had CMR as their initial test and were negative for ischemia. The detection of pericarditis in these 2 patient groups was assessed using LGE of the pericardium.

Results:
3,525 patients who presented with chest pain and no evidence of ACS underwent nuclear MPI. 347(9.8%) of these 3,525 patients had a normal nuclear MPI, but subsequently underwent a CMR for persistent chest pain and constituted Group A. 63 of 347(18.1%) Group A patients with a normal MPI had evidence of pericarditis on LGE. Group B had 505 patients with chest pain who underwent a CMR stress study, noting 461(82.4%) were normal, while 89(17.6%) had evidence of CAD. Of the 461 patients with a normal CMR stress, 80(19.2%) had evidence of pericarditis on LGE.

Conclusions:
About 10% of patients with CP and normal MPI may continue to complain of discomfort. These patients are usually labeled as “non-cardiac”, and often undergo gastrointestinal and musculoskeletal evaluation. Evaluation of this group of patients with CMR shows that 18-19% have pericarditis by LGE and are incorrectly labeled as “non-cardiac”. Newer treatments for pericarditis with colchicine/non-steroid anti-inflammatory drugs have high success rates, while undiagnosed/untreated pericarditis is likely a precursor to constrictive disease, making the need for a correct initial diagnosis imperative.
Abstract 12920: The Value of
18
FDG PET/CT in the Diagnostic Work-Up of Patients With Possible Infective Endocarditis
Authors: Chirillo Fabio , Boccaletto Franco , Pantano Paola , De Leo Alessandro , Possamai Marta , Inoiosa Walter O , Scotton Piergiorgio , Olivari Zoran
Published: July 2021

The diagnosis of infective endocarditis (IE) is sometimes difficult when there are discrepancies between blood cultures, transesophageal echocardiography (TEE) and clinical judgment. The aim of this study was to assess the incremental diagnostic value of
18
F-FDG-PET/CT in 45 consecutive patients (73% male, mean age 61 ± 26 years) with suspected IE and inconclusive tests at admission. In 28 patients (19 with a cardiac valvular (15) or nonvalvular (4) device) with blood cultures positive for germs typically involved in IE the initial TEE was negative or inconclusive. In 10 patients presenting with fever TEE identified cardiac lesion possibly related to IE (ruptured mitral chordae, thickened valve leaflet, thickened prosthetic annulus), but blood cultures were persistently negative. Finally, 7 patients had metastatic or embolic lesions and a predisposing cardiac condition, but TEE was negative. When previous unknown lesions detected by PET/CT were confirmed by succeeding examinations, they were considered true positives. When PET/CT was negative, it was compared with the final diagnosis that was defined according to the modified Duke criteria determined during a 6-month follow-up. Thirty patients had definite IE at the end of the follow-up, 3 had possible IE, and in 12 patients the diagnosis was rejected. Twenty-seven patients (60%) exhibited abnormal FDG uptake around the cardiac valves, and 12 (27%) had extracardiac accumulation. In 5 patients the initial negative TEE became positive a mean 5 ±7 days after PET/CT had been performed The sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT were as follows (95% confidence interval): 87% (68% to 95%), 67% (38% to 87%), 84% (65% to 94%), and 71% (42% to 92%), respectively. Adding abnormal FDG uptake as a new major criterion significantly increased the sensitivity of the modified Duke criteria at admission (68% [53% to 82%] vs. 96% [88% to 99%], p = 0.01). This result was due to a significant reduction (p < 0.001) in the number of possible IE cases. In conclusion PET/CT increases the diagnostic accuracy for IE in the subset of patients with possible IE and may help to manage a challenging situation.