bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11664: The Identification and Hierarchy of Bone Marrow-Derived Artery-Resident Mesodermal Progenitor Cells and Their Dynamics in Atherosclerosis
Authors: Cho Hyun-Jai , Cho Hyun-Ju , Kwon Yoo-Wook , Park Young-Bae , Kim Hyo-Soo
Published: July 2021

Background:
We recently identified bone marrow (BM)-derived artery resident calcifying progenitor cells. Sca-1+PDGFRα- cells may possess bipotent (osteoblastic/osteoclastic) characteristics. However, the nature of progenitor cells remains elusive.

Hypothesis:
We investigated developmental hierarchy of progenitor cells and
in vivo
dynamics in atherosclerosis.

Methods and Results:
We harvested cells from BM and artery of C57 mice. In BM, Lin-CD29+Sca-1+PDGFRα- cells showed hematopoietic potential and differentiated into osteoclasts (OC). They also possessed mesenchymal stem cell property including osteoblastic (OB) differentiation, suggesting that Sca-1+PDGFRα- cells could be mesodermal progenitor cells. Interestingly, BM-derived artery-resident, clonal Sca-1+PDGFRα- cells maintained bipotency but lost hematopoietic nature. In contrast, Sca-1+PDGFRα+ cells in BM and artery only showed unipotency (OB). When we overexpressed or knocked down PDGFRα, there was no alteration in OB or OC differentiation of Sca-1+PDGFRα- cells and no effect on OB differentiation of Sca-1+PDGFRα+ cells, indicating PDGFRα as a surface marker but not a functional player. In hyperlipidemic ApoE-KO mice compared with control, Sca-1+PDGFRα- cells were less mobilized from BM to peripheral circulation and less infiltrated into atherosclerotic plaque, whereas Sca-1+PDGFRα+ cells were not significantly affected. Multiplex cytokine assay of serum and artery revealed that IL-1β was significantly increased and IL-5 was markedly decreased in atherosclerotic mice. IL-1β decreased the migration of Sca-1+PDGFRα- cells by 5 folds compared with TNFα, and IL-5 increased the migration as much as TNFα. But the migration of Sca-1+PDGFRα+ cells was not altered. These data indicate that atherosclerosis-related humoral factors mainly regulated mesodermal progenitor cells’ dynamics.

Conclusion:
We demonstrate that Sca-1+PDGFRα- cell is a mesodermal progenitor cell that possesses both hematopoietic and mesenchymal potentials. In atherogenesis, the mobilization and infiltration of Sca-1+PDGFRα- progenitor cells were regulated by IL-1β and IL-5. These data provide a novel mechanism regarding the role of bipotent progenitor cells in atherosclerosis.
Abstract 11689: The Association Between Serum Potassium and Mortality in a Cohort of Patients With Diminished Kidney Function
Authors: Yang Alex , Luo Jiacong , Jensen Donna E , Brunelli Steven M
Published: July 2021

Introduction:
Serum potassium (K) is tightly regulated by the kidney between 3.5 and 5.0 mEq/L, which is essential for cardiac action potential and normal function. However, due to impaired excretory capacity, patients with chronic kidney disease (CKD) often have elevated serum K that potentially increases morbidity and mortality.

Hypothesis:
To better understand the burden of hyperkalemia and how this may vary by severity of renal disease, we studied the association of serum K with rates of mortality within narrow strata of estimated glomerular filtration rate (eGFR).

Methods:
We identified a retrospective cohort of patients with eGFR <60 mL/min/1.73m
2
between Jan-2009 and Jun-2013 (N=55,266). Patients were followed until 30-Jun-2013 or censoring (death, end-stage renal disease, transfer of care). Serum K, eGFR, and 13 covariates including demographics, comorbidities and medication use (beta blockers, centrally acting calcium channel blockers, loop and thiazide diuretics) were considered on a time-varying basis, updated at each K measurement. Death was considered as event per time at-risk.

Results:
At baseline, 15%, 4%, and 1% of patients had serum K 5.0-5.4, 5.5-5.9, and ≥6.0 mEq/L, respectively; prevalence was greater in lower eGFR strata. In each eGFR stratum, a U-shaped association between serum K and mortality was observed (figure shown for eGFR <30 mL/min/1.73m
2
). Compared to K 4.5-4.9 mEq/L, adjusted incidence rate ratios (IRRs) for K ≥6.0 mEq/L were 3.08 [95%CI, 2.17-4.37], 2.74 [1.13-6.74], 1.72 [0.76-3.86], and 3.90 [1.23-12.32] in eGFR <30, 30-39, 40-49, and 50-59 mL/min/1.73m
2
strata, respectively.

Conclusions:
Serum K ≥6.0 mEq/L is potently and independently associated with increased mortality among CKD patients. This association is independent of degree of kidney failure. Future population studies should examine cause-specific mortality according to hyperkalemia strata to identify possible mechanisms of cardiac death.
Abstract 11697: Hyperhomocysteinemia Induces CD40
+
Monocyte and Inflammatory Monocyte in Chronic Kidney Disease Subjects via DNA Hypomethylation-Related Mechanism
Authors: Yang Jiyeon , Kolli Abhigna C , Choi Eric T , Yang Xiao-Feng , Wang Hong
Published: July 2021

Hyperhomocysteinenia (HHcy) is associated with chronic kidney disease (CKD) which has increased cardiovascular disease (CVD) mortality and mobility. Elevated inflammatory monocyte (inf. MC) is a cellular hallmark of chronic inflammation which contributes to the burden CVD. We previously reported that HHcy induces inf. MC differentiation in mice and DNA hypomethylation in vascular cells. We assesses whether HHcy causes MC differentiation in CKD and the underlying mechanism.

Degree of CKD was determined by plasma creatinine from patients with peripheral vascular disease (VD). Estimated glomerular filtration rate was calculated with modification in age, race and gender. (VD, n=13; VD with CKD, n=13; Healthy donor without evidence of VD and CKD, n=13). Blood cells were assessed for phenotypic characterization by flow cytometry.

We found that plasma Hcy levels are elevated in VD and CKD. CD14++CD16+ inf. MC are increased in VD subjects and mild HHcy(>15μM). Plasma Hcy levels are positively correlated with inf. MC, CD40, TNF receptor family 5. We identify that CKD patient serum and Hcy (50μM) treatment increased CD40 in purified human blood MC by RT-PCR. Hcy metabolites, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), are increased in CKD subjects. SAM/SAH ratio, an indicator of methylation status, is reduced and is negatively correlated with Hcy, inf. MC, and CD40+ inf. MC. Hcy induced MC-origin inflammatory cytokines IL-6 mRNA in MC isolated from healthy donor by RT-PCR, and potentiated inflammatory cytokine IL-6, TNFα, and IFN[[Unable to Display Character: ɤ]]-induced CD40 expression in cultured PBMCs. Hcy suppressed CD40 transcription and reduced DNA methyltransferase 1 protein levels in cultured human MC. We identified four DNA hypomethylation CpG dinucleotides at p65 and PU.1 transcription factor consensus sequences on CD40 promoter in white blood cells isolated from CKD patients by Bisulfite pyrosequencing. Finally, CD40L levels are positively correlated with plasma Hcy and inf. MC. CD40 ligation by CD40L treatment (0.4μg/l) in peripheral blood mononuclear cells (PBMC) induced inf. MC differentiation.

We conclude that HHcy potentiates IFN[[Unable to Display Character: ɤ]]-mediated CD40 expression via CD40 DNA hypomethylation in CKD and promotes CD40-CD40L mediated inf. MC differentiation.
Abstract 11985: C1q / tnf-Related Protein 9 Protects Against Acute Myocardial Injury
Authors: Kambara Takahiro , Shibata Rei , Ohashi Koji , Joki Yuusuke , Hayakawa Satoko , Ito Mizuho , Yuasa Daisuke , Ouchi Noriyuki , Murohara Toyoaki
Published: July 2021

Background:
Obesity-related disorders are associated with an increased risk for cardiovascular disease. C1q/TNF-related protein (CTRP) 9 is an anti-diabetic adipokine that is downregulated in obese mice. Recently, we have reported that CTRP9 prevents adverse vascular remodeling in response to injury. Here, we investigated the effect of CTRP9 on acute cardiac injury with loss-of-function genetic manipulations.

Methods and Results:
CTRP9-deficient (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from Wild-type (WT) mice under basal conditions. CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory cytokines including TNF-α and IL-6 in ischemic heart following ischemia-reperfusion compared with WT mice. CTRP9-KO mice also had exacerbated contractile left ventricle (LV) dysfunction and increased myocardial expression of inflammatory cytokines following intraperitoneal injection of lipopolysaccharide (LPS) compared with WT mice. Conversely, systemic delivery of an adenoviral vector expressing CTRP9 (Ad-CTRP9) attenuated inflammatory responses to myocardial ischemia-reperfusion or LPS administration in WT mice. In cultured cardiac myocytes, treatment with CTRP9 protein suppressed LPS-stimulated expression of TNF-α and IL-6 with an accompanying reduction of NFkB phosphorylation. Treatment of cardiac myocytes with CTRP9 enhanced AMPK phosphorylation, and transduction with dominant-negative mutant form of AMPK reversed the suppressive effect of CTRP9 on TNF-α and IL-6 expression. Furthermore, systemic administration of Ad-CTRP9 improved LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK.

Conclusions:
These findings suggest that CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AMPK-dependent mechanisms.
Abstract 11989: Cardiac 12-Lipoxygenase-Induced Oxidative Stress Promotes the Development of Diabetic Cardiomyopathy
Authors: Kayama Yosuke , Suzuki Hirofumi , Sakamoto Masaya , Shimizu Ippei , Nagoshi Tomohisa , Minamino Tohru , Yoshimura Michihiro
Published: July 2021

Diabetes mellitus affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonic acid (AA) metabolism was thought to be a potential mediator of cardiac fibrosis and heart failure associated with oxidative stress. 12-lipoxygenase (12-LOX) is a key lipid peroxidizing enzyme of the AA cascade that plays an important role in the development of atherogenesis and neurodegenerative disease. However, the role of 12-LOX in diabetic cardiomyopathy has not been examined.

To determine whether 12-LOX is a key molecule in the development of diabetic cardiomyopathy, we created streptozotocin (STZ)-induced diabetic mice (WT-STZ) and compared to control mice. Cardiac expression of 12-LOX pathway was up-regulated after induction of diabetes. Histological analysis revealed that expression of 12-LOX was specifically up-regulated in cardiomyocytes but not vascular cells and fibroblast cells. Cardiac fibrosis was increased after induction of diabetes. We next created STZ-induced diabetic mice using 12-LOX KO mice (KO-STZ) and compared them to WT-STZ. Cardiac dysfunction and fibrosis in WT-STZ were significantly inhibited in KO-STZ.

We next examined the relationship between 12-LOX and cardiac oxidative stress in the diabetic heart. Cardiac expression of 4-hydroxy-2-nonenal (4-HNE) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) were up-regulated in the diabetic heart. This increase was inhibited by disruption of 12-LOX.

To further investigate the subcellular mechanism of the increase reactive oxygen species (ROS) in the diabetic heart, intracellular ROS levels in cardiomyocytes were estimated under high glucose condition (HG) and normal glucose condition (LG) by fluorimetry and using MitoTracker® Red in vitro. Cardiomyocytes under HG showed the enhancement of fluorescence intensity of DCF-DA and loss of mitochondrial membrane potential. Treatment with 12-LOX inhibitor (CDC) improved the enhancement of DCF-DA and mitochondrial membrane potential under HG condition.

These in vivo and in vitro results suggest that 12-LOX pathway is important in the process of production of ROS and oxidative stress in diabetic heart and promotes the development of diabetic cardiomyopathy.
Abstract 12027: Peripheral Endothelial Dysfunction Independently Correlated With Cardiovascular Events in Patients Following Coronary Stent Implantation
Authors: Tabata Noriaki , Hokimoto Seiji , Akasaka Tomonori , Arima Yuichiro , Kaikita Koichi , Nakagawa Kazuko , Ogawa Hisao
Published: July 2021

Introduction:
Percutaneous coronary intervention (PCI) is performed in patients with coronary heart disease to improve symptoms and clinical prognosis. Despite optimal therapies after PCI, some patients experience one or more adverse outcome. Therefore, to evaluate the determinants of the residual risk of cardiovascular events is still important. Endothelial dysfunction has been reported to correlate with adverse cardiovascular events in coronary heart disease.

Hypothesis:
We hypothesized that endothelial dysfunction could predict future cardiovascular events in patients following coronary stent implantation.

Methods:
We conducted a prospective cohort study of 435 patients after coronary stent implantation. All patients received aspirin and clopidogrel in addition to other optimal medications. Peripheral endothelial dysfunction was expressed as reactive hyperemia index (RHI) using reactive hyperemia peripheral arterial tonometry, and we used the median value of the RHI (0.54) to divide patients into low (n=218, male 70.2%) and high (n=217, male 70%) RHI groups. We followed cardiovascular events after coronary stent implantation.

Results:
There was no significant difference in clinical characteristics between the low and high group. A total of 64 patients had a cardiovascular event. The incidence of cardiovascular event was significantly higher in the low RHI group (20.2% versus 9.2%; P=0.007). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 70 months; log-rank test: P=0.002). Multivariate Cox hazard analysis among various clinical factors demonstrated that body mass index (hazard ratio [HR]: 0.906; 95% confidence interval [CI]: 0.838 to 0.980; P=0.014), peripheral arterial disease (HR: 1.834; 95% CI: 1.003 to 3.351; P=0.049), Cytochrome P450 loss-of-function allele carriage (HR: 2.005; 95% CI: 1.101 to 3.651; P=0.023), and RHI (HR: 0.149; 95% CI: 0.044 to 0.502; P=0.002) as independent and significant determinants of clinical outcome.

Conclusions:
Peripheral endothelial dysfunction independently correlated with future cardiovascular events in patients following coronary stent implantation.
Abstract 121: Quality of Cardiopulmonary Resuscitation by Bystanders and Survival After Out-of-Hospital Cardiac Arrest
Authors: Nishiyama Chika , Kitamura Tetsuhisa , Shimamoto Tomonari , Kawamura Takashi , Sakamoto Tetsuya , Iwami Taku
Published: July 2021

Introduction:
Although quality of cardiopulmonary resuscitation (CPR) is a key to increase survival after out-of-hospital cardiac arrest (OHCA), little is known about the quality of bystander CPR and its association with survival outcomes after OHCA.

Objective:
To evaluate the association of quality of bystander CPR and patient outcomes after OHCA.

Methods:
Designs: Population-based cohort study. Cases: All OHCA cases treated by emergency medical services (EMS) personnel in Toyonaka city between September 2011 and August 2013. Data collection and analyses: EMS personnel assessed bystanders’ CPR quality including hand position, depth, and tempo of chest compressions using a specific data form at the scene. Fleiss’ Kappa statistics was used to assess the evaluation reliability among EMS personnel and the Kappa value was 0.81 before the study. The primary outcome was patient one-month survival with favorable neurological outcome and it was compared between the good-quality CPR group and the poor-quality CPR group.

Results:
Among 877 cases, bystander CPR was attempted in 429 (48.9%). Data on quality of CPR was applicable in 272 (63.4%) of them. In the good-quality CPR group, bystanders were younger, more likely to be health care provider, and have experience of CPR training than in the poor-quality of CPR group. The proportion of patients with neurologically favorable one-month survival was somewhat greater in the good-quality of CPR group (4.6% versus 3.0%), although it was statistically insignificant.

Conclusions:
Better quality of bystander chest compressions might increase OHCA patient survival. Further efforts to improve quality of CPR by general public are needed.
Abstract 12158: Population Thresholds for Systematically Applying Nurse-Led Chronic Heart Failure Management Programs to Reduce Recurrent Hospitalization and Prolong Survival
Authors: Stewart Simon , Gerber Tracey , Chan Yih Kai , Carrington Melinda ,   on behalf of the WHICH? Trial Investigators
Published: July 2021

Background:
In many countries, a jurisdictional (regional or health fund membership) approach to applying nurse-led, multidisciplinary management programs for high risk individuals hospitalized with chronic heart failure (CHF) has led to their inconsistent application. A health service perspective was therefore used to determine the overall value of funding services for a whole population.

Methods:
Data from a contemporary study of the burden of CHF in Australia (population ~ 24 million of whom ~25% live in regional settings) to identify the number of de novo admissions for CHF per annum (n=19,397) were used. From these we estimated the proportion of cases readmitted (63% - all cause), days of related hospitalization (44,500 days from 5,300 admissions) and case-fatality (27%) within 12 months. Health economic data from a recent multicentre trial of CHF management were then applied to estimate the cost impact ($US) of applying gold-standard management to de novo CHF cases.

Results:
Total health care expenditure (excluding index admission and incremental CHF management) for managing de novo cases of CHF is estimated at ~$300 million/annum. Of this total, $240 million (68%) is attributable to hospital care plus device-based therapies. Applying nurse-led multidisciplinary CHF management to all cases (with up-titration of therapy and increased face-to-face and remote contacts as required) would cost ~ $35 million/annum. In order to achieve a cost-neutral state, this service would need to achieve a minimum reduction of 6,500 days (15% reduction) in recurrent hospital stay (all cause). At proven, evidence-based thresholds of impact, a 20% - 30% reduction in recurrent hospital stay would provide annual savings of $12 - 35 million/annum. A one third reduction in mortality at 12 months would also result in 2,100 lives saved at a minimum cost >$17,000 per annum (neutral impact on recurrent hospital stay).

Conclusions:
These data provide a compelling case for adopting a whole population/health care system approach to systematically applying CHF management programs to reduce recurrent hospital stay and mortality in de novo cases of CHF.
Abstract 12177: Inhaled Nitric Oxide During Cardiopulmonary Resuscitation Improves Functional Outcome and Increases 7-Day-Survival After Prolonged Cardiac Arrest in Rats
Authors: Brücken Anne , Bleilevens Christian , Derwall Matthias , Fries Michael
Published: July 2021

Introduction:
Precordial compressions during cardiac arrest (CA) increase pulmonary vascular resistance (PVR), potentially impeding survival by limiting left ventricular preload. Although used as selective pulmonary vasodilator there is accumulating evidence that inhaled nitric oxide (iNO) also attenuates I/R injury.

Hypothesis:
Applying iNO during cardiopulmonary resuscitation (CPR) increases resuscitation rates and improves functional outcome after cardiac arrest in rats.

Methods:
Thirty male Sprague-Dawley rats were subjected to 10 mins of CA and 3 mins of CPR. Animals were randomized to receive either 20 ppm or 40 ppm iNO during CPR until 30 mins after ROSC (return of spontaneous circulation) or no iNO treatment. For all animals a neurological deficit score (NDS) was calculated daily for seven days following the experiment.

Results:
Inhalation of 20 ppm iNO increased ROSC rates in comparison to animals treated with 40 ppm or without iNO treatment, however this failed to reach statistical significance (control: 7/10; 20ppm iNO: 10/10; 40ppm iNO 6/10). 20 ppm iNO significantly decreased time to ROSC, resulting in a significant reduction of post-arrest lactate levels. Also, significantly higher mean arterial pressures in comparison to control animals were observed. Furthermore, 20 ppm iNO resulted in a significantly higher seven-day-survival in comparison to controls (control: 4/10; 20 ppm iNO: 10/10). All iNO treated animals showed better neurological outcomes, being significant in animals treated with 20 ppm iNO on postoperative day 2- 7.

Conclusions:
Our study demonstrates that 20 ppm but not 40 ppm iNO during CPR significantly decreases time to ROSC. Furthermore, significantly better seven-day-survival and neurological outcome was noted for 20 ppm iNO in comparison to controls.
Abstract 12185: Restoration of Autophagy in Endothelial Cells From Patients With Diabetes Improves Nitric Oxide Signaling
Authors: Fetterman Jessica L , Flint Nir , Holbrook Monica , Linder Erika A , Berk Brittany D , Duess Mai A , Feng Bihua , Farb Melissa G , Gokce Noyan , Shirihai Orian S , Hamburg Naomi M , Vita Joseph A
Published: July 2021

Diabetes is associated with oxidative stress and decreased nitric oxide bioactivity in the vasculature. Autophagy is a critical multistep pathway that eliminates damaged proteins and organelles from the cell. Emerging evidence suggests impaired autophagy in non-vascular tissues contributes to the pathogenesis of diabetes. We hypothesized that impaired autophagy contributes to endothelial dysfunction associated with diabetes in humans. We measured vascular function and autophagy markers in freshly isolated endothelial cells (ECs) from patients with diabetes and non-diabetic controls. Diabetes was associated with endothelial dysfunction characterized by lower brachial artery flow-mediated dilation and impaired activation of eNOS by insulin in ECs. ECs from diabetic patients had higher levels of p62 (Figure), a protein that accumulates with reduced autophagic flux. Measures of autophagy initiation including rapamycin stimulation, beclin 1 levels, and LC3 puncta were not different. Global activation of autophagy with spermidine reversed endothelial dysfunction in freshly isolated ECs from diabetic patients (Figure). In ECs from controls, inhibiting autophagy with bafilomycin impaired eNOS activation confirming that intact autophagy promotes NO signaling. Evidence from cultured endothelial cells in high glucose conditions suggested that lysosomal function is intact as measured by lysosomal number and acidification. Blocking the terminal step of autophagy with bafilomycin in ECs from diabetics led to a further accumulation of p62, suggesting intact but insufficient levels of autophagy. Lamp2a, which facilitates the merger of autophagosomes and lysosomes, was higher in diabetic cells, possibly reflecting a compensatory response to reduced flux. These findings provide evidence for inadequate autophagic flux in ECs from diabetic patients that contributes to impaired NO signaling and may be a target for therapy of diabetic vascular disease.
Abstract 12252: Effects of the Cholesteryl Ester Transfer Protein Inhibitor, Evacetrapib, Administered as Monotherapy or in Combination With Statins on Cholesterol Efflux and HDL Particles in Patients With Dyslipidemia
Authors: Rader Daniel J , Ruotolo Giacomo , Kane John P , Wang Ming-Dauh , Krueger Kathryn A , Nissen Steven E , Nicholls Stephen J , Brewer Bryan H
Published: July 2021

Objectives:
The CETP inhibitor evacetrapib (EVA) has been shown to substantially increase HDL-C and apoA-I levels as monotherapy and combined with statins. The effects of EVA on cholesterol efflux capacity and HDL particle distribution have not been described and were evaluated in this study.

Methods:
Samples from patients (n=398) with elevated LDL-C or low HDL-C enrolled in the multicenter, randomized, double-blind, parallel, placebo-controlled trial (JAMA 2011;306:2099-2109, NCT01105975) were studied. Percent changes from baseline in cholesterol efflux capacity (global, ABCA1- and non-ABCA1-mediated), preβ HDL (measured by immunofixation and 2D-gel), and other HDL subclasses (measured by 2D-gel and NMR) were evaluated after 12 weeks of placebo (PBO), statins alone, EVA alone, and EVA with statins.

Results:
Results are shown in the table. Statins alone decreased global and ABCA1-mediated cholesterol efflux and preβ-1 HDL (by 2D-gel). EVA alone and combined with statins increased global (28% and 21%, respectively), ABCA1- (17% and 15%, respectively), and non-ABCA1-mediated (35% and 27%, respectively) cholesterol efflux. EVA alone increased preβ-1 as measured by 2D-gel (20%) and immunofixation (32%); EVA combined with statins increased preβ-1 as measured by 2D-gel (27%). While statins alone had no significant effect on large and very large HDL (α-1 and α-2 HDL by 2D-gel, and large HDL by NMR), EVA alone and combined with statins increased these more buoyant HDL particles. Statins alone and EVA alone had no effect on small HDL, whereas EVA combined with statins significantly decreased small HDL particles as measured by NMR.

Conclusion:
In subjects with elevated LDL-C or low HDL-C, EVA alone and combined with statins increased global, ABCA1- and non-ABCA1-mediated cholesterol efflux. This improved global cholesterol efflux capacity was accompanied by a significant increase in preβ-1 and large and very large HDL particles.
Abstract 12325: Compensatory Increase of Left Atrial External Work to Left Ventricular Dysfunction During Afterload Increase: Insights Into the Mechanism of Decompensation in Heart Failure With Preserved Ejection Fraction
Authors: Inoue Katsuji , Asanuma Toshihiko , Masuda Kasumi , Sakurai Daisuke , Oka Masamichi , Kotani Koichiro , Higaki Jitsuo , Nakatani Satoshi
Published: July 2021

Introduction:
Afterload mismatch is considered as a cause of acute decompensation in patients with heart failure with preserved ejection fraction (HFPEF). However, behaviors of left atrium (LA) and ventricle (LV) to afterload increase have not been fully elucidated. We investigated how LA and LV acted to acute increase in afterload using speckle tracking echocardiography.

Methods:
Serial echocardiographic and hemodynamic data were acquired in 10 dogs during banding of the descending aorta (AoB). LA pressure was measured by a micromanometer via left pulmonary vein. As shown in Figure, peak negative strain during LA contraction and strain change during LA relaxation (early reservoir strain) and that during systole (late reservoir strain) were generated by simultaneous acquisition of LA longitudinal strain and volume. Pressure-strain curve showed 2 loops (A-loop, V-loop) and areas in A-loop and V-loop were computed as the work during active contraction and relaxation (A-work) and that during passive filling and emptying (V-work), respectively.

Results:
AoB increased LV systolic pressure by about 60 mmHg, mean LA pressure (3.8±1.3 vs. 7.1±2.0 mmHg) and LV end-diastolic pressure (4.5±1.7 vs. 10.7±4.0 mmHg, all p < 0.01). LV global circumferential strain decreased (-18.8±3.5 vs. -13.2±3.5%, p < 0.01) but LV stroke volume was maintained (8.4±2.3 vs. 9.6±3.6 ml). LA peak negative strain (-2.9±2.3 vs. -9.8±4.0%, p < 0.01) and early reservoir strain (3.4±1.1 vs. 7.8±2.6%, p < 0.01) increased substantially by AoB, but late reservoir function did not change (9.3±3.5 vs. 6.1±2.0%). A-work significantly increased (3.2±2.0 to 19.2±15.1 mmHg %, p < 0.01), while V-work did not change (13.3±7.1 vs. 13.6±8.0 mmHg %).

Conclusions:
During aortic banding, LA contraction, early reservoir function and thereby external work during the phase increased as a compensation to LV dysfunction. The failure of this mechanism may lead to decompensation in HFPEF.
Abstract 12368: Clinical Features, Prognosis and Risk Stratification of Acute Myocardial Infarction Due to Coronary Embolism
Authors: Shibata Tatsuhiro , Noguchi Teruo , Kawakami Shoji , Ishihara Masaharu , Goto Yoichi , Ogawa Hisao , Yasuda Satoshi
Published: July 2021

Introduction:
Coronary embolism (CE) is recognized as an important non-atherosclerotic cause of acute myocardial infarction (AMI). Atrial fibrillation (AF) is associated with systemic thromboembolism, and the CHADS2 and CHA2DS2-VASc scores are known to be useful for risk stratification. Therefore, we investigated the clinical features and prognosis of CE, and assessed the potential usefulness of these scores for predicting CE.

Methods:
We studied a total of 2,115 consecutive patients with AMI (M/F 1,528/587, age 68±12 [SD] years) hospitalized between 2001 and 2013. CE was diagnosed according to the criteria shown in Figure 1

Results:
The overall prevalence of CE in AMI was 2.4% (n=51, M/F 31/20, age 65±14 years). Compared with non-CE AMI patients, CE patients were characterized as lower prevalence of risk factors. Most common cause of CE was AF (73%). However, only 15 (41%) out of 37 AF patients were treated with vitamin K antagonists (VKAs) and their PT-INR was low, 1.42 (range, 0.95-1.80) at the onset of AMI. Importantly, among 28 CE patients with nonvalvular AF, 17 patients (59%) had a CHADS2 score of 0 or 1. When those particular patients were re-evaluated by CHA2DS2-VASc score, 10 out of 17 (59%) were categorized into a higher risk category (≥ 2) that would benefit from VKAs therapy. During a median follow-up of 4.1 years (interquartile range, 1.5-7.0 years), 8 patients (16%) had major adverse cardiovascular events and 5 patients (10%) recurred CE or systemic embolization (Figure 2).

Conclusions:
AF is the major underlying cause of CE, recurrence of which seems to be not rare. The CHA2DS2-VASc score may provide reliable risk stratification with a superior ability to predict CE.
Abstract 12381: Advantage of Aortic Valve Reconstruction in Dynamic Changes of Aortic Annulus Assessed by Speckle Tracking Echocardiography After Aortic Valve Surgery
Authors: Hashimoto Go , Suzuki Makoto , Yoshikawa Hisao , Otsuka Takenori , Isekame Yukiko , yamashita Hiromasa , Shiba Masanori , Iijima Raisuke , Hara Hidehiko , Ozaki Shigeyuki , Nakamura Masato , Sugi Kaoru
Published: July 2021

Introduction:
It is reported that aortic valve reconstruction (AVrC) by using autologous pericardium is useful in patients with various aortic valve diseases. This method may be more effective in preserving the natural motion of the aortic valve annulus. Significant dynamic changes in the aortic annulus have previously been reported in animal models and clinical studies. The purpose of this study is to analize the cyclic changes of the aortic annulus using speckle-tracking trans-esophageal echocardiography in patients who underwent AVrC surgery.

Methods:
The subjects were 35 patients underwent AVrC surgery for aortic regurgitation or aortic stenosis and 40 controls. Cyclic aortic annulus diameter of the maximum and minimum diameters were determined from a speckle-tracking displacement curve (figure). These data was used to calculate the absolute change in the diameter of the aortic annulus, which was defined as the difference in diameters throughout the cardiac cycle.

Results:
There was significant difference between maximum and minimum aortic annulus diameter in AVrC group (18.7±3.0 mm vs 16.1±2.9 mm, p<0.0001). There was significant difference in the maximum and minimum aortic annulus diameter in control group (22.9±2.7 mm vs 20.0±2.9 mm, p<0.0001). AVrC group had significant cyclic change of aortic annulus as same as control group (AVrC group : 2.6±1.0 mm vs control group : 2.9±0.7 mm, p= NS).

Conclusions:
Our study suggests that dynamic changes of the aortic annulus occur in the cardiac cycle and can be measured using speckle-tracking trans-esophageal echocardiography. AVrC may preserve the coordination of the left ventricle, aortic annulus, sinus of Valsalva and aorta compared with conventional aortic valve replacement.
Abstract 12390: Right Heart Failure Predicts Higher Mortality in Patients With Hypertrophic Cardiomyopathy
Authors: McCullough Stephen A , Shimada Yuichi J , Baggish Aaron L , Lowry Patricia A , O’Callaghan Caitlin , Rothman Richard D , Vlahakes Gus J , Fifer Michael A
Published: July 2021

Introduction:
The clinical correlates of right heart failure (RHF) and its association with mortality in hypertrophic cardiomyopathy (HCM) have not been reported previously.

Methods:
We performed a retrospective cohort study of patients in our HCM program who underwent right heart catheterization between 1997 and 2012. RHF was assessed by right atrial pressure (RAP). Clinical correlates assessed were mean pulmonary artery pressure (PAP), mean pulmonary capillary wedge pressure (PCWP), atrial fibrillation (AF), ventricular tachycardia/fibrillation (VT/VF), and mortality. Data were analyzed with linear regression for PAP and PCWP, logistic regression for AF and VT/VF, and the Cox-proportional hazards model and the log-rank test for mortality.

Results:
147 patients (age 68 ± 14 years, 54% women) were included in the study, with median follow-up for mortality 7.0 years. Median RAP was 6 mmHg [interquartile range, 4-9 mmHg]. Higher RAP was associated with higher PAP (+7.4 ± 0.8 mmHg per 5 mmHg increase, p < 0.001) and PCWP (+5.0 ± 0.5 mmHg per 5 mmHg increase, p < 0.001). Higher RAP was associated with prior AF (odds ratio [OR] = 1.6 [1.05 - 2.5] per 5 mmHg increase, p = 0.03) and prior VT/VF (OR = 1.6 [1.04 - 2.4] per 5 mmHg increase, p = 0.03). Higher RAP was found to predict overall mortality (hazard ratio [HR] = 2.5 [1.2 - 5.0] per 5 mmHg increase, p = 0.01). When data were dichotomized, RAP > 10 mmHg was associated with increased mortality (p = 0.002, Figure).

Conclusions:
(1) As in other causes of heart failure, RHF in HCM is associated with higher PAP and PCWP. (2) RHF in HCM is associated with a higher prevalence of AF and VT/VF. (3) RHF in HCM is associated with increased mortality.
Abstract 12438: Novel 4-Dimensional Optical Technique to Elucidate Hemodynamic Shear Forces and Initiation of Trabeculation During Cardiac Morphogenesis
Authors: Lee Juhyun , Fei Peng , Jen Nelson , Beebe Tyler , Ho Chih-ming , Marsden Alison , Chi Neil , Hsiai Tzung
Published: July 2021

Hemodynamic shear forces are intimately linked with cardiac development. However, the mechano-transduction mechanisms underlying this morphological event remain elusive. Trabeculation develops after cardiac looping, which is visualized in zebrafish embryos starting at 70 hours post-fertilization (hpf). We hypothesized that endocardial wall shear stress (WSS) up-regulates Notch signaling to initiate trabeculation. We developed a novel fast z-axis imaging acquisition system to reconstruct time-dependent 3-dimensional WSS in live zebrafish using single plane illuminating microscopy (SPIM). To assess the link between shear stress and trabeculation, we lowered the WSS by micro-injection of (1) gata1a-morpholino oligonucleotides (MO) at 2-cell stage to reduce erythropoiesis and viscosity by 70%, (2) tnnt2a-MO injection to inhibit cardiac contraction, and (3) use of weak atrium(wea) mutant to inhibit atrial contraction. To determine mechano-signal transduction underlying WSS and trabeculation, we assessed Notch signaling by in situ hybridization of NRG1 and notch1b. At 70 hpf, the control fish showed formation of trabeculation, whereas gata1 MO injected fish revealed a decrease in trabeculation in response to a reduction in shear stress by 90 %. Both wea mutant and tnnt2a MO injected fish exhibited smooth endocardial surfaces without trabecular networking. In situ hybridization of NRG1 and Notch 1b further showed a decrease in fluorescent intensity in the gata1 MO, wea mutant, and tnnt2a MO groups by 2.33±0.87-fold, 4.21±0.25-fold, and 4.96±0.17-fold, respectively (p < 0.05 vs. control fish, n=10). Thus, our findings indicate that hemodynamic shear forces are implicated in the initiation of cardiac trabecualtion via Notch signaling pathway, with a translational implication to understanding congenital noncompacted cardiomyopathy.
Abstract 125: "Load & Go" Criteria in Out-of-Hospital Cardiac Arrest Patients for the Use of Emergency-Extracorporal Life Support at the Emergency Department
Authors: Poppe Michael , Schober Andreas , Weiser Christoph , Sulzgruber Patrick , Datler Philip , Keferböck Markus , Zeiner Sebastian , Lobmeyr Elisabeth , Nürnberger Alexander , Van Tulder Raphael , Krammel Mario , Sterz Fritz
Published: July 2021

Background:
The outcome of patients after OHCA has been poor. The probability of return of spontaneous circulation decreases over time. New therapeutic attempts like E-ECLS at the ED are tried to improve outcome of selected cases. The "Vienna Cardiac Arrest Registry" (VICAR) was introduced August 1, 2013 to collect Utstein-style data. Our aim was to identify those patients which might fulfill ‘load&go’ criteria for E-ECLS at the ED after OHCA.

Methods:
Therefore VICAR was retrospectively analysed for following criteria: age<75a;witnessed OHCA; basic life support (BLS); ventricular fibrillation/ventricular tachycardia (VF/VT); no return of spontaneous circulation (ROSC) within 15min CPR by EMS. Patients had to fulfill all these criteria.

Results:
Overall 701 patients were registered from August 1, 2013 to April 30, 2014. Excluded were because of poor documentation 26(4%) patients, because of missing criteria data 49(7%) and because they were younger than 18 years 7 (1%). The final analysis included 619(88%) patients; of those 68(11%) were transported under ongoing CPR to the ED. Moreover E-ECLS was applied in 15 patients at the ED.

Conclusion:
We found 30 (5%) patients to fulfill ’load & go’ criteria. Of 68 patients, who were transported with ongoing CPR to the ED only 8 (8%) met the criteria. Further promotion of these criteria within the ambulance crews is needed. Maybe these criteria could then serve as a decision support for emergency physicians/paramedics, which patients to transport under ongoing CPR to the ED for E-ECLS.
Abstract 12553: Telmisartan, a Clinically Available Anti-Hypertensive Medicine, Enhances Mitochondrial Function and Improves Endothelial Dysfunction Through the AMPK Pathway
Authors: Kurokawa Hirofumi , Sugiyama Seigo , Nozaki Toshimitsu , Sugamura Koichi , Toyama Kensuke , Matsubara Junichi , Fujisue Koichiro , Ohba Keisuke , Maeda Hirofumi , Yamamoto Eiichirou , Tsujita Kenichi , Kaikita Koichi , Hokimoto Seiji , Ogawa Hisao
Published: July 2021

Background:
Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. Telmisartan (TELMI) is a unique angiotensin II type I receptor blocker (ARB) that has clinically been shown to prevent cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function leads to improvement of endothelial function via AMPK, and could improve endothelial function in mice and human.

Methods and Results:
In cultured human coronary artery endothelial cells (HCAECs), TELMI significantly increased the phosphorylation of AMPK (1.61±0.45 fold, p<0.05) and endothelial nitric oxide synthase (eNOS) (1.39±0.23 fold, p<0.01), and enhanced mitochondrial function as assessed by both mitochondrial reductase activity (1.22±0.15 fold, p<0.01) and ATP production (1.16±0.93 fold, p<0.05). TELMI prevented cellular senescence (senescence associated β-galactosidase staining assay: 0.61±0.14 fold, p<0.01) and enhanced angiogenic activity (tubular formation: 1.73±0.25 fold, p<0.01). These effects by TELMI were abolished by both pharmacological and genetical inhibition of AMPK. In a mouse model of metabolic syndrome, TELMI prevented high fat diet (HFD)-induced endothelial dysfunction, as shown by acetylcholine-induced vascular relaxation (HFD: 74.5±3.3%, HFD+TELMI: 84.8±3.2% P<0.05), and increased the phosphorylation of AMPK (1.28±0.13 fold, P<0.05) and eNOS (1.27±0.16 fold, P<0.05) in aortas. In hypertensive patients, switching treatment from other ARB or angiotensin converting enzyme inhibitors to TELMI improved endothelial function assessed by reactive hyperemia on peripheral arterial tonometry index (pre-TELMI: 0.40±0.14, post-TELMI 0.54±0.17, p<0.05).

Conclusions:
TELMI significantly enhanced mitochondrial function and exhibited anti-senescent activity via AMPK in HCAECs, and improved endothelial function in mice and human. The vascular protective effects induced by TELMI may partly be due to its enhancement of mitochondrial function and reduction of endothelial senescence by AMPK.
Abstract 12587: An Improved Approach to Cardiac Volumetrics: A Cardiac MRI Technique to Further Augment Accuracy
Authors: Rayarao Geetha , Biederman Robert W , Thompson Diane V , Reddy Sahadev T , Yamrozik June , Williams Ronald B , Doyle Mark
Published: July 2021

Introduction:
In cardiac MRI (CMR), heart volumes are traditionally measured using contouring methods applied to contiguous image data. Herein, we introduce a new approach, Automatic Threshold and Manual Trimming (ATMT), which is applied to the same contiguous data set. Potentially, the ATMT method can be applied by seed/region-growing algorithms with minimal user supervision. We sought to establish its clinical validity.

Hypothesis:
We hypothesize that the ATMT approach is more accurate as compared to conventional 'gold standard', cardiac contouring.

Methods:
Hearts from two populations (N=74) were evaluated: explanted heart transplant (Tx) and a clinical validation cohort (
in vivo
). The transplanted hearts were imaged
ex vivo
using CMR and then weighed on a high-fidelity scale. Cardiac volume/mass was compared (N=54) to the patient cohort (N=20) and measured non-invasively with stroke volume, independently measured via CMR phase velocity technique. Bland-Altman was applied in a 3-way manner for each group.

Results:
Bland-Altman analysis for Standard Deviation (SD), Bias and Correlation (R) are summarized in Table 1. When compared with independent measurements (weight/flow), ATMT has lower Bias (close to zero) and SD. Further, any comparison involving cardiac contours has a substantially larger bias term and a higher SD. From the table below, ATMT has consistently higher correlations with the independent measurement than does the contour method.

Conclusions:
Based on multiple comparison metrics with independent measures, the ATMT approach is more accurate and reproducible for quantification of cardiac volume (integral for EF determination) as compared to standard contouring. Furthermore, ATMT accommodates trabeculae and papillary structures more intuitively than the contouring method. This intrinsic accuracy coupled with the potential for more rapid analysis gives a valid impetus to further develop the ATMT approach further increasing CMR accuracy.
Abstract 12605: Center Variability in Timing of Stage 2 Palliation and Association With Interstage Mortality: A Report From the National Pediatric Cardiology Quality Improvement Collaborative
Authors: Hill Garick , Rudd Nancy , Ghanayem Nancy , Hehir David , Bartz Peter
Published: July 2021

Introduction:
The interstage period from discharge following stage 1 palliation (S1P) until stage 2 palliation (S2P) remains high risk. Significant variability between institutions exists around the timing of S2P. We sought to describe the variability in a multi-institution cohort and assess its association with interstage mortality.

Methods:
The National Pediatric Cardiology Quality Improvement Collaborative registry, with data from 52 centers, was queried. Patients undergoing a hybrid S1P, transplanted prior to S2P, lost to follow up prior to S2P or deemed not candidates for S2P were excluded. Only centers with 10 or greater patients meeting eligibility were included to reduce the impact of outliers. Centers were divided based on median age at S2P into early (n=15) and late (n=16) centers using a cutoff of 153 days. Groups were compared using Chi-squared or Wilcoxon rank sum test.

Results:
The final cohort included 789 patients from 31 centers. Center specific median age at S2P varied from 109 to 214 days, with a center mean of 158 ± 27 days. At S1P, the late centers had a higher prevalence of preoperative ventilation (34.7% vs. 26.9%, p=0.02) and longer average post-S1P duration of intubation (14.4 ± 19.7 vs. 10.2 ± 11.4 days, p<0.001) and S1P hospital length of stay (48.5 ± 30.4 vs. 38.5 ± 22.3 days, p<0.0001). Interstage mortality was significantly higher in centers performing late vs. early S2P (9.9% vs. 5.7%, p=0.03). Interstage event rate (late: 8.2 vs. early: 5.8 deaths per 10000 interstage days) was not different by group (p=0.26), but interstage duration was significantly longer (133.9 ± 71.5 vs. 103.4 ± 37.8 days, p<0.0001) in the late group. Survival to hospital discharge (98.9% in both groups, p>0.98) and hospital length of stay following S2P (late: 15.6 ± 22.3 vs. early: 13.7 ± 22.4, p=0.68) were similar between groups.

Conclusions:
In a large multi-institution collaborative, the median age at S2P varies between centers. Centers performing S2P at a later median age have higher interstage mortality. This may be in part due to a higher severity of illness, reflected by higher S1P morbidity in this group. Although optimal timing of S2P remains unclear, centers performing early S2P did not experience worse S2P outcomes, and experienced less interstage mortality.
Abstract 12651: Atrium Fibrosis and Inflammation: Impaired Atrial Natriuretic Peptide System in Experimental Heart Failure
Authors: Ichiki Tomoko , Huntley Brenda K , Sangaralingham S Jeson , Harty Gail J , Burnett John C
Published: July 2021

Introduction:
The cardiac atrium is an important endocrine organ which also releases natriuretic peptides (NPs). We reported that dysregulation of the proNP convertases, furin and corin, may disrupt NP progressing, causing atrial fibrosis in experimental heart failure (HF). Atrial fibrosis results in atrial arrhythmias and impairs the prognosis of human HF, therefore understanding mechanisms of atrial fibrosis may help in designing treatment strategies for HF. We sought to extend our studies into the entire NP system and global gene profiles including fibrotic and inflammatory pathways in experimental HF.

Hypothesis:
Components of the NP, pro-fibrotic and inflammatory system will be up-regulated in the atrium in HF.

Methods:
Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days. We examined hemodynamics, echo parameters, circulating neurohumoral factors, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, inflammation and cardiac hypertrophy in left atrium (LA) from normal and HF canines (n=4 of each).

Results:
Experimental HF was characterized by decreased % EF and LV radial strain, and increased circulating ANP, cGMP and aldosterone levels. HF LA weight significantly increased with fibrosis and interstitial edema compared to normals. Gene profile analyses showed increases in profibrotic cytokines and extracellular matrix related genes in LA. Increased ANP expression but also increased ANP degrading enzyme IDE and decreased proANP processing enzyme corin were also observed. Genes related to inflammatory cytokines such as TNF-alpha, members of the IL-6 family, MCP-1, and cell adhesion molecules were up-regulated in LA compared to normals.

Conclusions:
Experimental HF was characterized by on-going atrial fibrosis with increased circulating ANP levels. Although ANP gene expression increased in failing LA, impaired proANP processing and accelerated ANP degradation may impair any anti-fibrotic ANP effects. Further, atrium may be a source of inflammatory cytokines and pro-fibrotic growth factors which may advance organ damage in HF. Our studies suggest NP treatment, perhaps in a form less susceptible to IDE degradation, may be a novel therapeutic for HF.