bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15475: Elevated Plasma levels of Neutral Endpeptidase in Hypertension Patients Treated with Angiotensin Converting Enzyme Inhibitors
Authors: Sugamura Koichi , Sugiyama Seigo , Fujisue Koichiro , HIrata Yoshihiro , Kurokawa Hirofumi , Maeda Hirofumi , Yamamoto Eiichiro , Tsujita Kenichi , Kaikita Koichi , Hokimoto Seiji , Ogawa Hisao
Published: July 2021

Background:
Inhibiting Neutral Endpeptidase-24.11 (NEP) combined with angiotensin receptor blocker (ARB) has recently been employed as an effective treatment for hypertension (HT). Although soluble form of NEP (sNEP) is able to measure in human plasma, the relationship between plasma levels of sNEP and clinical condition is still unknown in HT patients.

Methods:
We consecutively measured plasma levels of sNEP and B-type natriuretic peptide (BNP) in 210 patients with HT (144 male, 66 female, mean age; 69.5±10.4) who were suspected cardiovascular disease with multiple risk factors from April 2013 to December 2013. The levels of plasma sNEP were measured by using commercially available ELISA kits (SEB785Hu, USCN life science inc.).

Results:
Plasma levels of sNEP were non-normally distributed in whole high-risk HT patients assessed by Shapiro-Wilk test (p<0.01, median; 431.7 pg/ml, interquartile range; 302.0 to 540.9 pg/ml). sNEP levels were not significantly different among the patients with or without CAD [n=176, 431.7 pg/ml, (310.7 to 532.1) vs. n=34, 437.1 pg/ml, (284.4 to 574.6), p=0.851]. Plasma levels of sNEP were significantly greater in the HT patients treated with angiotensin converting enzyme inhibitors (ACEI) compared with those treated without ACEI [n=46, 493.4 pg/ml, (395.2 to 614.0) vs. n=164, 403.4 pg/ml, (299.6 to 523.8), p=0.012]. Plasma levels of sNEP were not significantly different between the patients with or without using ARB [n=107, 397.7 pg/ml, (284.8 to 506.8) vs. n=103, 456.4 pg/ml, (335.0 to 568.0), p=0.098]. There is no significant association between the plasma levels of sNEP and log BNP (ρ=0.018, P=0.801). Multivariable logistic regression analysis revealed that the administration of ACEI was independently associated with the higher levels of sNEP above median (odds ratio=2.48, 95% confidence interval; 1.23 to 5.03, p<0.02).

Conclusion:
Among high risk patients with HT, patients treated with ACEI demonstrated significantly elevated levels of sNEP and the administration of ACEI was independently associated with the higher levels of sNEP. NEP could be up-regulated by ACEI and ARB did not significantly affect on NEP activity in HT patients. NEP could be effectively inhibited by a NEP-inhibitor in HT patients treated by ARB.
Abstract 15483: Regenerative Effects of Exosomes Secreted by Cardiospheres in a Rat Model of Chronic Myocardial Infarction Are Mimicked by Exosome-primed Fibroblasts
Authors: Tseliou Eleni , Fouad Joseph , de Couto Geoffrey , Middleton Ryan , Weixin Liu , Valle Jackelyn , Ibrahim Ahmed , Marbán Eduardo
Published: July 2021

Background:
Multicellular self-assembling cardiospheres (CSps) exert regenerative and anti-fibrotic effects via paracrine mechanisms. CSp-derived cells are known to secrete exosomes which mediate most or all of the beneficial therapeutic effects.

Objective:
We evaluated the regenerative capacity of CSp-secreted exosomes in a model of chronic myocardial infarction (MI). We also determined whether CSp-exosomes could convert the phenotype of therapeutically-inert cells.

Methods:
Exosomes were isolated from CSp-conditioned media by adding a precipitation solution followed by centrifugation. One month post-MI, Wistar Kyoto rats (n=46) with permanent LAD ligation were injected intramyocardially with: a) human dermal fibroblasts (DFs), b) CSp exosomes, c) DFs primed with CSp-exosomes, d) CSps only or e) vehicle. Functional and histological analyses were performed 4 weeks after therapy. Mechanisms were also probed
in vitro
.

Results:
In vivo,
CSp-exosomes and CSps equally increased ejection fraction (EF= 45±1% [CSp-exo], 44±2% [CSps], 33±1% [placebo] and 35±2% [DFs]) and reduced scar mass (48±8mg [CSp-exo], 45±4mg [CSps], 96±12mg [placebo] and 90±6mg [DFS]; both p<0.01 by one way ANOVA). DFs that had been incubated with CSp-exosomes for 24 hours in culture conferred enhanced benefits compared to unprimed DFs (EF= 41±1% [primed-DFs]; p=0.05 vs unprimed DFs; scar mass= 49±5mg [primed-DFs]; p<0.01 vs unprimed DFs). Confocal imaging revealed internalization of fluorescently-labeled CSp-exosomes in exosome-primed DFs.
In vitro
, exosome-primed DFs increased tube formation by HUVECs and inhibited cardiomyocyte apoptosis. Immunohistochemistry showed increased vessel density in all groups compared to vehicle or unprimed DFs.

Conclusions:
Administration of CSp-exosomes recapitulates the regenerative potential and functional benefits of CSps themselves. The surprising ability of CSp-exosomes to confer therapeutic efficacy on inert DFs may represent an unanticipated amplification mechanism for exosome-mediated benefits.
Abstract 15489: Hematopoietic PI3-Kinase δ-Deficiency Exacerbates Lesional Macrophage Infiltration and Atherosclerosis in LDLR-/- Mice
Authors: Zierden Mario , Millarg Christopher , Vantler Marius , Berghausen Eva , Baldus Stephan , Rosenkranz Stephan
Published: July 2021

Atherosclerosis and its consequences such as myocardial infarction and ischemic stroke remains the leading cause of death in western countries. Atherosclerosis is a chronic inflammatory disease of arterial blood vessels, critically involving macrophages, dendritic cells and T lymphocytes. Leukocytes highly express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), exerting a key role in the regulation of immune responses including activation, differentiation and effector function of lymphocytes. Therefore, PI3Kδ represents a promising target for the modulation of inflammatory processes during atherogenesis.

To investigate the role of leukocytic PI3Kδ during atherogenesis, lethally irradiated LDLR
-/-
mice were either transplanted with bone marrow from PI3Kδ
-/-
or PI3Kδ
+/+
mice. After recovery, recipient mice were fed an atherogenic diet for 6 weeks. Hypercholesterolemic PI3Kδ
-/-
recipient LDLR
-/-
mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4
+
T-cell activation, T-helper 1 response and regulatory T-cell numbers in paraaortic lymph nodes and spleen compared with PI3Kδ
+/+
transplanted controls. Surprisingly, the profound impairment of the adaptive immune system by PI3Kδ-deficiency caused a considerable aggravation of atherosclerosis in LDLR
-/-
mice. Atherosclerotic lesion area at the aortic root and abdominal aorta of PI3Kδ
-/-
recipient LDLR
-/-
mice was significantly increased by 72% and 218% compared with PI3Kδ
+/+
recipients, respectively (n = 10[[Unable to Display Character: –]]20;
P
< 0.001). Importantly, atherosclerotic lesions of PI3Kδ-deficient LDLR
-/-
mice were characterized by a lower fraction of CD4
+
T cells and a higher proportion of MOMA-2
+
monocytes/macrophages compared with controls despite unaltered circulating monocyte subsets. Thus, PI3Kδ-deficiency in mononuclear phagocytes may contribute to enhanced plaque growth.

In summary, we demonstrate that hematopoietic PI3Kδ plays a crucial role in regulating innate and adaptive immune responses within the arterial wall by exerting protective functions during atherogenesis. Current studies aim to dissect PI3Kδ-dependent mechanisms that modulate inflammatory and regulatory processes in multiple stages of atherosclerosis.
Abstract 15571: Suppressing Increased Expression of NADPH-Dependent Malic Enzyme 1 in Hypertrophied Hearts Eliminates Maladaptive Anaplerosis and Improves Redox Conditions
Authors: Lahey Ryan , Fischer Susan K , Wang Xuerong , Bi Jian , Carley Andrew N , O’Donnell J Michael , Lewandowski E Douglas
Published: July 2021

The remodeled metabolic phenotype of hypertrophic hearts includes inefficient glucose oxidation, due in part to pyruvate carboxylation into anaplerosis. Increased carboxylation of pyruvate to malate via elevated malic enzme-1 (ME1) also consumes NADPH, which is necessary for maintaining glutathione reduction. Therefore, we studied the consequences of selective inhibition of ME1 expression via non-native miRNA targeted to the ME1 gene (miRME1) in hypertrophied rat hearts after transverse aortic constriction (TAC). TAC elevated ME1 content, but ME1 was lowered in hearts receiving miRME1 vs PBS infusion (*P<0.01). The effects of ME1 suppression on anaplerosis and GSH content were studied in isolated hearts supplied 13C palmitate, glucose, and lactate. While Sham miRME1 hearts showed no further reduction of inherently low baseline ratios of anaplerosis to citrate synthase flux from normal hearts, miRME1 reduced anaplerosis in TAC to baseline: TAC miRME1=0.034±0.004; TAC PBS=0.081±0.005 (*P<0.01, **P<0.001). Importantly, ME1 suppression restored GSH in TAC (†P<0.05). The findings demonstrate the maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied hearts, and thus consumption of NADPH for anaplerotic malate, produced favorable metabolic shifts, improving intracellular redox state.
Abstract 15578: The Combination of an Ostium Secundlum Type Atrial Septal Defect with a Pulmonary Arterial Thromboembolism Caused an Enlarged Pulmonary Artery, Pulmonary Hypertension and Recurrent Paradoxical Cerebral Embolism due to Deep Vein Thrombosis
Authors: Funabashi Nobusada , Takaoka Hiroyuki , Ozawa Koya , Tanabe Nobuhiro , Tatsumi Koichiro , Kobayashi Yoshio
Published: July 2021

A 65 year old female was referred to our hospital with dyspnea on effort. When she was 42 years old, she was diagnosed by transthoracic echocardiology (TTE) with an ostium secundlum type atrial septal defect (ASD) with a pre-existing right to left shunt through the ASD. When she was 60 years old, she was diagnosed with a brain abscess due to a paradoxical cerebral embolism and admitted to our brain surgery ward a total of three times. The diagnosis was confirmed and treatment with Clopidogrel sulfate was started. Six months ago, she felt dyspnea on effort and gradually worsened. She was referred to our department for further examination. Chest X ray revealed cardiac enlargement with a cardiothoracic ratio of 61%. Serum d dimer and brain natriuretic peptide were elevated to 3.3μg/ml and 492pg/mL, respectively. TTE showed an enlarged PA, right atria (RA) and right ventricle (RV) with a thickened RV wall. A bidirectional shunt through a large ASD could also be observed. PA systolic pressure was estimated, by the pressure gradient from tricuspid valve regurgitation, at 94mmHg. CT revealed an enlarged, calcified PA with a mural thrombus, enlarged and thickened RV wall and a right to left shunt through the ASD. The LV was compressed by the RV, suggesting RV pressure load. Because a mural thrombus was observed in the PA, CT acquisitions of the lower extremities were added 3 minutes after contrast injection. An enlarged popliteal vein with a deep venous thrombus (DVT) was observed. Tadalafil was prescribed for pulmonary hypertension to improve oxygen concentration. Heparin followed by warfarin was administered for the DVT and mural thrombus in the PA.

At follow up, CT showed no change to the mural thrombus in the PA, therefore home oxygen therapy was started.

From experience of this case, and in subjects with Eisenmenger ASD, if severe PA dilation and PA hypertension and paradoxical cerebral embolism are detected, one should also suspect PA thromboembolism due to DVT.
Abstract 15632: The Implications of the Recent American College of Cardiology/American Heart Association Guidelines for the Treatment of Blood Cholesterol on a Rural Community: The Heart of New Ulm Project
Authors: Miedema Michael D , Sidebottom Abbey C , Sillah Arthur , Benson Gretchen , Boucher Jackie , Knicklebine Tom , VanWormer Jeffrey J
Published: July 2021

Introduction:
The impact of the new American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines on the volume of statin-eligible patients requires further analysis, particularly in rural communities who are rarely included in traditional large observational cohorts.

Methods:
We performed a cross-sectional analysis using data from the Heart of New Ulm Project, a population-based program aimed at reducing modifiable cardiovascular disease (CVD) risk factors in rural New Ulm, MN. According to 2010 census data, there were 7,855 adults aged 40-79 years in the target population at that time. The community is served by one health and electronic health records (EHR) system. EHR-based demographics, diagnoses, and medications were analyzed in residents aged 40-79 years in 2012-2013. The prevalence of indications for statin therapy and of use of statins and other lipid-lowering medications were analyzed according to the ACC/AHA guidelines.

Results:
There were 6,357 residents with a visit during the study period, of which 4,281 had adequate data and were included in the analysis (mean age 59.4 [10.2] years, 52.7% female). In our study sample, 2,529 (59%) met one of the 4 major indications for statin therapy (Table). Of those with an indication, 65% were on a statin, 11% were on a high-intensity statin, and 5% on other lipid-lowering agents. An age stratified analysis demonstrated that 86% of individuals 60-79 years old (n=2,036) are now statin-eligible compared to 35% of individuals 40-59 years old (n=2,245).

Conclusion:
Using contemporary EHR data from a rural Midwest community, approximately 3 in 5 middle-age residents qualify for statin therapy according to the new guidelines, but only two-thirds of those individuals were taking a statin. Full compliance with the new guidelines will require a significant increase in statin utilization, including more frequent use of high-intensity statins.
Abstract 15709: Bivalirudin is Associated With Decreased Cardiovascular Outcomes and Bleeding as Compared to Heparin During PCI: A Meta- Analysis
Authors: Patel Pawan , Arora Bhaskar , Molnar Janos , Khosla Sandeep , Arora Rohit
Published: July 2021

Background:
Anticoagulant therapy is needed for safe and effective Percutaneous Coronary Intervention (PCI). Bivalirudin is widely used as an anticoagulant during PCI in acute coronary syndromes. Prior analysis had shown significant decrease in bleeding with similar rates of death with Bivalirudin compared to Heparin. Recent studies have shown mixed results. We performed this meta-analysis to compare the effect of bivalirudin versus heparin on major bleeding and deaths after PCI.

Methods:
We performed a systematic literature search for studies comparing bivalirudin versus heparin on major bleeding and deaths after PCI. Studies providing data on the outcome of major bleeding and deaths were included. Statistical heterogeneity across the various trials was tested using the Cochran’s Q statistic and I2 was computed to quantify heterogeneity. A two-sided alpha error of less than 0.05 was considered to be statistically significant (p < 0.05).

Results:
Total of 22 eligible studies was included for major bleeding events and total 24 eligible studies were included for death events. The studies for major bleeding events were heterogeneous while studies for death events were homogenous; hence random and fixed effect model was used respectively to calculate combined relative risk (RR). Meta-analysis revealed that the use of bivalirudin compared to heparin is associated with statistically significant lower rates of major bleeding (RR, 0.612; CI, 0.504 to 0.742; p = 0.000) and death (RR, 0.709; CI, 0.606 to 0.830; p = 0.000).

Conclusion:
Our analysis concluded that bivalirudin compared to heparin is associated with lower rates of major bleeding and death during PCI.
Abstract 15724: Intermittent Hypoxia Induces Early Pro-Atherogenic Changes in Aortic Wall Macrophages in a Murine Model of Obstructive Sleep Apnea
Authors: Gileles-Hillel Alex , Almendros Isaac , Khalyfa Abdelnaby , Zhang Shelley , Wang Yang , Gozal David
Published: July 2021

Background:
OSA is a highly prevalent condition throughout the lifespan, and has emerged as an independent risk factor for atherosclerosis. Macrophages play a key role in the pathogenesis of atherosclerosis through shifts in the continuum between the pro-inflammatory M1 and the athero-protective M2. We hypothesized that Intermittent Hypoxia (IH) during the sleep period, a model for OSA, will induce shifts towards a pro-atherogenic state in the spectrum of macrophages within the aortic vascular wall.

Methods:
8-week old male C57BL/6J mice were exposed to IH for 12-hr/day during the light period or to room air (RA) for 6 weeks and were kept on a regular low-fat chow. Following exposure, full-length aortas were dissected and enzymatically digested. Single cell suspensions were prepared and cells were incubated with antibodies for macrophage markers previously implicated in atherogenesis and metabolic dysregulation - CD11b, F4/80, Ly6c, CD36, and CD64, and analyzed by FACS.

Results:
Macrophages were defined as CD11b+/F4/80+ cells. Significant increases in the percentage of macrophages emerged in IH-exposed mice (6.4%±0.3 vs. 8%±0.3, p=0.003, n=19-20/group). Furthermore, IH induced shifts in the macrophage population toward an M1 pro-inflammatory phenotype. Specifically, IH group showed significantly higher expression of Ly6c, (MFI:522±23 vs. 699±43, p=0.004, n=12/group) and increased the percentage of Ly6c+(hi) cells (9.2% vs. 11.7%, p=0.03). Conversely, tissue-resident marker CD64 expression in the aortic macrophages was down-regulated following IH exposures (MFI:3207±453 vs. 2967±483, p=0.03, n=12/group), while scavenger receptor CD36 expression was increased in the IH-exposed group (MFI:1694±56 vs.2129±209, p=0.005).

Conclusion:
Intermittent hypoxia during the sleep period leads to early expansion of the macrophage population in the aortic wall in a relatively resistant animal model for development of atherosclerosis, i.e., in the absence of a high-fat diet or of high atherogenic risk predisposing gene knockout. Furthermore IH induces changes in macrophage phenotypes, including a shift towards a pro-inflammatory phenotype, and recruitment of bone-marrow derived macrophages expressing indicators of metabolic activation.
Abstract 15741: Long Term Survival Following Transcatheter Aortic Valve Replacement: Results From a Single US High Volume Center
Authors: Escarcega Ricardo O , Torguson Rebecca , Magalhaes Marco A , Baker Nevin C , Minha Sa’ar , Lipinski Michael J , Lhermusier Thibault , Ota Hideaki , Satler Lowell , Pichard Augusto , Ben-Dor Itsik , Waksman Ron
Published: July 2021

Introduction:
Mortality following Transcatheter aortic valve replacement (TAVR) has been reported up to 5 years. However, mortality after 5 years remains unclear.

Hypothesis:
We aim to determine the mortality in patients undergoing TAVR >5 years follow up.

Methods:
From our institution’s prospectively collected TAVR database we analyzed all patients undergoing TAVR to a maximum follow up of 8 years. We divided our population into transapical TAVR (TA-TAVR) and transfemoral TAVR (TF-TAVR) groups. A Kaplan-Meier survival analysis was conducted.

Results:
A total of 511 patients who underwent TAVR were included in the analysis. Patients undergoing TA-TAVR had higher rates of peripheral vascular disease compared with TF-TAVR (56% vs 29%, p<0.001) and Society of Thoracic Surgeons Score (10.9 ± 4 vs 9.2 ± 4, p<0.001). TA-TAVR was associated with higher mortality at 1 year (32% vs 21%, p=0.01). However, there was no significant difference in very-long term mortality of patients undergoing TA-TAVR vs TF-TAVR (Figure).

Conclusions:
Long-term mortality following TAVR surpasses 50%. While in the first 2 years TA-TAVR is associated with higher mortality rates after three years the survival rates are similar in both approaches.
Abstract 15742: Predicting Outcomes After Percutaneous Mitral Balloon Valvotomy: The Impact of Left Ventricular Strain Imaging
Authors: Barros-Gomes Sergio , Eleid Mackram F , Dahl Jordi S , Pislaru Cristina , Nishimura Rick A , Pellikka Patricia A , Pislaru Sorin V
Published: July 2021

Introduction:
Presence of subclinical left ventricle (LV) dysfunction may influence outcomes after percutaneous mitral balloon valvotomy (PMBV), but cannot be detected by conventional echocardiography.

Hypothesis:
Preprocedure LV global longitudinal strain (GLS) by speckle tracking TTE detects subclinical LV dysfunction and predicts long-term outcome after successful PMVB.

Methods:
Consecutive patients undergoing PMBV between 2003-2011 who had comprehensive baseline TTE were included. Patients with suboptimal immediate results (repeat PMBV or mitral surgery within first 6 months) and those with suboptimal TTE strain were excluded. LV strain was analyzed with commercial software (Syngo VVI), and GLS averaged from 18 segments. The primary end point was all-cause mortality. Secondary end point was the composite of death and mitral valve reintervention.

Results:
Of 110 patients screened, 29 (26%) had unsuitable strain imaging, and 8 (7%) had poor immediate results, leaving 73 in the final cohort. Median follow-up was 3.7 years (interquartile range 1.3-7.2). There were 10 deaths (14%) and 25 late mitral valve interventions (34%). Univariate predictors of death were GLS, age, EF, stroke volume, pulmonary artery pressure, mitral valve area and coronary artery disease. In a multivariate Cox model, GLS was the strongest predictor of death after adjustment for age [HR=1.40 (1.09-1.84), P=0.008]. For the composite endpoint, GLS, mitral valve gradient, and invasively mean left atrial pressure were univariate predictors of death or reintervention. At multivariate analysis, GLS was the sole predictor of events [HR=1.17 (1.01-1.34), P=0.03]. Event-free survival is shown in figure. Intra and inter observer intra-class correlation for strain analysis was 0.87 (0.66-0.96) and 0.84 (0.53-0.95), respectively.

Conclusions:
GLS is a powerful predictor of long-term outcome after PMVB and appears to have an incremental prognostic value over traditional parameters.
Abstract 15863: Macrophage Foxp1 is a Regulator of Pathologic Cardiac Hypertrophy
Authors: Yoneda Shuichi , Haldar Saptarsi M , Jenkins Jessica , Wang Yunmei , Inoue Teruo , Jain Mukesh K , Shi Can , Simon Daniel I
Published: July 2021

Introduction:
Pathologic cardiac hypertrophy is a maladaptive response to neurohormonal and hemodynamic stress that is a hallmark of human heart failure. While inflammation has been implicated in pathologic hypertrophy, the molecular mechanisms underlying innate immune dysregulation in this disease process are incompletely defined. We have previously demonstrated that the forkhead transcription factor Foxp1 controls monocyte differentiation and suppresses inflammatory activation of macrophages. In this study, we hypothesized that monocyte/macrophage Foxp1 regulates pathologic cardiac hypertrophy.

Methods:
Macrophage-specific Foxp1 over-expressing (macFoxp1tg=anti-inflammatory) vs. non-tg controls, as well as macrophage-specific Foxp1 knockdown (macFoxp1ko=pro-inflammatory) vs. Cre-control male mice were subject to chronic angiotensin II (AII) infusion (1.8 mcg/kg/min via subcutaneous osmotic mini-pump) for 4 weeks.

Results:
AII-mediated cardiac hypertrophy (heart mass and cardiomyocyte cross-sectional area), left ventricular (LV) systolic dysfunction, LV dilation, interstitial fibrosis and macrophage (Mac-3+ cells) accumulation were significantly attenuated in macFoxp1tg mice compared to non-tg controls. In contrast, AII-mediated cardiac hypertrophy, LV systolic dysfunction and cavity dilation were significantly exacerbated in macFoxp1ko mice compared to Cre controls. There were no differences in systemic blood pressure between these groups, corroborating a load-independent role for macrophage Foxp1 in cardiac hypertrophy.

Conclusion:
These studies identify macrophage Foxp1 as a novel negative regulator of pathologic cardiac hypertrophy in vivo. Modulation of Foxp1 signaling may provide a novel strategy for prevention and treatment of heart failure.
Abstract 15884: Cardiosphere-Derived Cells Confer Acute Cardioprotection Following Ischemia-Reperfusion Injury in Rats: Role of Macrophage Polarization
Authors: de Couto Geoffrey , Kanazawa Hideaki , Tseliou Eleni , Marbán Linda , Marbán Eduardo
Published: July 2021

Introduction:
Cardiosphere-derived cells (CDCs) confer both cardioprotection and regeneration in acute myocardial infarction (MI). However, only long-term (>3 wks) post-MI endpoints have been studied, making it impossible to investigate the cardioprotective effects in isolation. Macrophages (MF) concentrate within the heart following ischemic injury as part of the inflammatory response to injury. Here we test the hypothesis that CDCs are cardioprotective by modifying MF within the myocardium post-MI.

Methods & Results:
Wistar-Kyoto rats (aged 8-12 wks) underwent 45 min of ischemia followed by 20 min of reperfusion, then intracoronary (i.c.) infusion of either saline or CDCs (5x10
5
). The use of a 48 hr endpoint enabled the selective study of cardioprotection. CDC-treated animals had preserved ejection fraction (59.2% vs. 47.4%; p<0.001) and reduced infarct size (TTC; 6.3% vs. 13.6%; p<0.01). The finding that CDC-treated hearts contained fewer CD68
+
MF (p<0.05) suggested a mechanistic role for MF, a conjecture which we tested in detail. MF isolated from CDC-treated hearts secreted lower amounts of proinflammatory cytokines (
Nos2, Tnf, Il1b
; p<0.05). Systemic depletion of MF with clodronate liposomes attenuated the benefits of CDC therapy post-MI (p<0.05).
In vitro
, MF conditioned by transwell exposure to CDCs (M
CDC
) exhibited distinct gene profiles relative to proinflammatory M
1
or “healing” M
2
polarization states (M
CDC
:
Il10
; M
1
:
Nos2
; M
2
:
Arg1, Pparg
). Adoptive transfer of selective MF populations into the heart (i.c.; 20 min post-reflow) revealed that M
CDC
, but not M
1
or M
2
MF, could recapitulate the reduction in infarct size (M
CDC
: 4.5%; M
1
: 14.0%; M
2
: 10.8%; p<0.05).
In vitro
co-culture shows that M
CDC
selectively reduce cardiomyocyte apoptosis following oxidant stress (M
CDC
: 9.9%; M
1
: 39.4%; M
2
: 37.4%; p<0.001).

Conclusions:
CDCs are cardioprotective when administered 20 min after reflow; the timing distinguishes this form of cardioprotection from preconditioning or ischemic postconditioning. Various lines of evidence indicate that CDCs work by polarizing MF toward a cardioprotective phenotype. The findings motivate further translational development of the adjunctive use of CDCs post-MI to limit infarct size.
Abstract 15907: Disruption of HCN2 Leads to Laterality Defects and Cardiac Arrhythmia
Authors: Ye Bin , Taycher Greg , Hacker Tim , Chan Leslie , Shi Nian-Qing
Published: July 2021

Background:
Congenital heart defects (CHDs) encompass a large numbers of cardiovascular malformations, and remain the major cause of infant mortality among all types of birth defects. However, molecular mechanisms underlying CHDs remain elusive, largely owning to the complexity of the diseases and lack of animal models that can reproduce the pathophysiological conditions in a laboratory setting. The hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCN) are responsible for generating spontaneous pacemaker activities in cardiac and central nervous systems. These channels are also detected in other cell types such as ventricular myocytes. HCN currents recorded from neonatal cells have an activation threshold of -70 mV while those recorded from adult cells are activated at -110 mV. This difference indicates that HCN activity might be important in early development. However, roles of HCN channels in cardiogenesis and development are not fully understood.

Methods and Results:
We created a HCN2 conditional knockout (HCN2KO) model in which the full-length HCN2 was disrupted. Two KO lines were subsequently derived from this model. The first line was weaned by 21 days and they all died by 4-5 wks of age. Maternal ultrasound study revealed that these KO mice developed fetal arrhythmia and had an underdeveloped left side in their hearts. The second line was able to live on under our special diet/care. These mice displayed a slower growth rate (1.1±0.2 g/wk) and lower body weight (15.1±2.0 g) relative to their age-matched WT controls (2.2±0.1 g/wk and 27.5±1.5 g; n=9-10, p<0.05). Echocardiography and tissue staining data suggested that KO hearts had laterality defects compared to their size-matched WT controls. The survived KO mice were able to maintain cardiac function by developing much thicker anterior and posterior walls to sustain blood-pumping (n=6, p<0.05). Electrocardiographic results indicated that the average heart rate recorded from KO mice was ~100 bpm slower than their age-matched WT controls (n=5-6, p<0.05).

Conclusions:
These novel findings indicate that HCN2 is indispensable in mouse cardiogenesis and development. Our KO models are therefore innovative platforms for future CHD research.
Abstract 15927: Successful Pharmacological Cardioversion by Oral Amiodarone Therapy is Correlated With Favorable Post-Ablation Clinical Outcomes in Non-Paroxysmal Atrial Fibrillation
Authors: Otomo Kiyoshi , Takizawa Kaname , Inoue Naoto , Meguro Taiichiro
Published: July 2021

Backgrounds:
Catheter ablation (CA) for non-paroxysmal atrial fibrillation
(AF)(non-PAF)
is less successful in patients (pts) with highly remodeled atria. It is still controversial that how far CA should be indicated in non-PAF pts with highly remodeled atria. Impacts of successful pharmacological cardioversion of non-PAF by oral amiodarone
(AMD)
on post-CA clinical outcomes remain to be evaluated.

Purposes:
To assess efficacy of oral AMD and implications of successful cardioversion by AMD in advance to CA on post-CA clinical outcomes in non-PAF pts.

Methods:
In consecutive 418 non-PAF pts (age: 63±9 years, AF duration: 28±37 months, LA diameter: 44±5mm), oral AMD (300 mg/day for 2 weeks and 100 mg/day thereafter) was initiated at outpatient clinic one month prior to the initial CA procedure. Recurrence-free survival after last CA procedure was compared between those with successful pharmacological conversion to sinus rhythm, atrial flutter or atrial tachycardia by the time of the initial CA procedure
(Group non-AF)
and those without
(Group AF)
.

Results:
At the beginning of initial CA procedure, 79 pts were in sinus rhythm, 8 in typical atrial flutter, 3 in atrial tachycardia
(Group non-AF: 90 pts (22%))
and the remaining 328 still in AF
(Group AF: 78%)
. During follow-up period of 287±204 days after last CA procedure (procedure number:1.6±0.7/pt, range: 1-4), 45 pts (11%) were followed up while taking AMD, whereas the other 373 pts (89%) without any antiarrhythmic drugs. Kaplan-Meier analysis revealed that recurrence-free survival after last CA procedure was significantly higher in Group non-AF than in Group AF
(88 (98%) vs. 291 (89%) pts; p=0.02)
. Group non-AF pts exhibited significantly shorter AF duration
(9±9 (range: 1-46) vs. 33±41 months (range: 1-240): p<0.0001)
and smaller LA diameter
(42±5 (range: 28-54) vs. 44±5 mm (range: 31-61): p<0.0001)
as compared with those in Group AF pts.

Conclusions:
Successful cardioversion by AMD in advance to CA was correlated with higher recurrence-free survival after last CA procedure. This simple criterion is helpful to find pts with less remodeled atria and good candidates for CA who will benefit from CA in non-PAF pts.
Abstract 16013: Direct Nkx2-5 Transcriptional Repression of Isl1 Controls Cardiomyocyte Subtype Identity
Authors: Goedel Alexander , Dorn Tatjana , Lam Jason T , Herrmann Franziska , Haas Jessica , Bundschu Karin , Dobreva Gergana , Schiemann Matthias , Dirschinger Ralf , Kühl Susanne J , Sinnecker Daniel , Moretti Alessandra , Kühl Michael , Laugwitz Karl-Ludwig
Published: July 2021

During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the LIM-homeodomain transcription factor Islet-1 (Isl1) and the homeobox protein Nkx2-5.

Here, we show that a direct repression of Isl1 transcription by Nkx2-5 is necessary for proper specification and maturation of ventricular and atrial chamber-specific myocardial lineages. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in the Isl1+ precursor population. These effects were partially rescued by Isl1 overexpression. Embryos deficient for Nkx2-5 in the Isl1+ lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube (Figure 1A). We demonstrated that Nkx2-5 directly binds to an Isl1 gene enhancer and represses the transcriptional activity of Isl1. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, Isl1 overexpression in ESCs leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased number of cardiomyocytes (Figure 1B). Functional and molecular analysis of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts (Figure 1C), which was associated with upregulation of nodal-specific genes and downregulation of transcripts of working myocardium.

Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors towards the different myocardial lineages and ensures proper acquisition of myocyte subtype-identity (Figure 1D).
Abstract 16054: Ventricular-Arterial Coupling Biphasically Correlates to Ventricular Diastolic Chamber Stiffness in Children–Association With Aldosterone Activation
Authors: Masutani Satoshi , Kim JeongHye , Kuwata Seiko , Kurishima Clara , Saiki Hirofumi , Tamura Masanori , Senzaki Hideaki
Published: July 2021

Introduction:
Left ventricular–arterial coupling (LVAC), the ratio of end–systolic to effective arterial elastance (Ees/Ea), determines end–systolic pressure and stroke volume in a given preload. LV diastolic chamber stiffness (LV–K) is an important diastolic property to affect LV filling. However, the relationship between Ees/Ea and LV–K in children remains unestablished. Aldosterone (ALD) accelerates LV and arterial stiffening.

Hypothesis:
This study was undertaken to test the hypothesis that Ees/Ea may affect LV–K through ALD regulation in children.

Methods:
During catheterizations for children with biventricular circulation (N=75, median 2.5 years), blood samples for ALD were collected, and LV pressure and area relationships (PAR) were recorded using high-fidelity pressure–guidewire and echocardiographic AQ method during steady state and transient IVC occlusion. LV–K was obtained by dividing the pressure difference between LV minimal and end-diastolic pressure (EDP) by stroke volume. ALD levels were transformed into common logarithm.

Results:
Ees/Ea biphasically correlated to LV–K, which was approximated by downward convex parabola with a minimum at 0.9 of Ees/Ea (R=0.61, P<0.0001). Ees/Ea also bipahsically correlated to log ALD, which was approximated by downward convex parabola with a minimum at 0.8 of Ees/Ea (R=0.45, P<0.005). Moreover, LV–K linearly correlated to log ALD (R=0.38, P<0.005). There was no significant relationship between LV–K and relative wall thickness.

Conclusions:
To our knowledge, this is the first study to demonstrate that Ees/Ea bipahsically correlated to LV–K and ALD. Dilated LV with low Ees/Ea accompanies elevated filling pressure and shows restrictive physiology with higher LV–K. On the other hand, when Ees/Ea is higher than normal range, this study indicates that there should be an increased LV diastolic stiffness which is not always associated with wall hypertrophy. Because LVAC abnormality may induce LV stiffening associated with ALD activation, chronic inhibition therapy of renin–angiotensin system to keep Ees/Ea within appropriate range may inhibit LV stiffening directly and through LVAC & LV–K interaction.
Abstract 16099: Influence of Nutritional Status on Depressive Symptoms and Quality of Life in Patients With Heart Failure
Authors: Tsuchihashi-Makaya Miyuki , Fukushima Arata , Kinugawa Shintaro , Kinugasa Yoshiharu , Ono Taisuke , Matsuo Hisashi , Okada Akiko , Kato Masahiko , Yamamoto Kazuhiro , Tsutsui Hiroyuki
Published: July 2021

Introduction:
The important goal of heart failure (HF) management is to improve quality of life (QoL) and psychological status. Nutrition is a key component of HF management, but information on the impact of nutrition in HF is limited. Moreover, there is little evidence that nutritional status affects QoL and psychological status.

Hypothesis:
This study tested the hypothesis that nutritional status is associated with QoL and depressive symptoms in HF patients.

Methods:
A cross-sectional study was conducted in 102 HF patients (mean age: 68.4 ±13.1 years, male: 66%). QoL and depressive symptoms were assessed by the Minnesota Living with Heart Failure (MLWHF) questionnaire and Patient Health Questionnaire-9 (PHQ-9), respectively. Nutritional status was assessed by the Mini Nutritional Assessment (MNA) long version and patients were categorized as well nourished (≥24 points), at risk of malnutrition (17-23.5 points), or malnourished (<17 points). Data on sociodemographic and clinical characteristics were also collected. Multiple linear regression analysis was performed to evaluate the association of nutritional status with depression and QoL.

Results:
In total, 50% patients were at risk of malnutrition and 2% were malnourished. HF patients at risk of malnutrition were more likely to have a history of valve surgery, implantable cardiac defibrillation (ICD), or smoking. Risk of malnutrition was not associated with left ventricular ejection fraction (LVEF) or brain natriuretic peptide (BNP) (P = 0.100 and P = 0.173, respectively). Malnourished patients or those at risk of malnutrition had significantly lower QoL and more depressive symptoms than well-nourished patients (QoL: 14.2 ± 13.9 vs 23.2 ± 17.9, P = 0.007; depressive symptoms: 4.49 ± 4.7 vs 2.02 ± 2.9, P = 0.002). In multiple linear regression analysis, these significant associations remained after controlling for age, sex, HF etiology, smoking, ICD therapy, LVEF, and BNP.

Conclusions:
Risk of malnutrition was associated with lower QoL and higher depressive symptoms in HF patients. This study confirmed that good nutrition was an important goal in HF management. Further research is required to identify key nutrients and dietary habits affecting QoL and psychological status in HF patients.
Abstract 161: Effectiveness of Lower Target Temperature Therapeutic Hypothermia for Post--Cardiac Arrest Victims Within 30 Minutes Resuscitation Interval
Authors: Kaneko Tadashi , Kasaoka Shunji , Nagao Ken , Yonemoto Naohiro , Yokoyama Hiroyuki , Nonogi Hiroshi
Published: July 2021

Introduction:
Therapeutic hypothermia (TH) for post cardiac arrest syndrome (PCAS) patients is standard strategy to reduce brain damage. However, current randomized control study (TTM: Target temperature management study, N Engl J Med 2013) suggested that simple target temperature did not improve outcome. Furthermore, there is no evidence, whether target temperature would be changed for each status of PCAS patients.

Hypothesis:
Lower target temperature could improve neurological outcome in PCAS patients.

Methods:
Participants with J-PULSE-Hypo study database were divided into the L group (32.0-33.9°C) and the M group (34-35°C). The favorable neurological outcomes (%, CPC 1-2 on 30th day) were compared between L and M groups in all and each subgroups with propensity score analysis with IPTW (inverse probability of treatment weighting) method as multivariate analysis. The subgroups were ages and interval from collapse to ROSC (return of spontaneous circulation).

Results:
477 participants were analyzed. The comparison of each groups for favorable neurological outcome were that all groups (L: 64%, n = 42, vs M: 55%, n= 424, P = 0.234, multivariate: P = 0.452), age (≤60 y.o.) (L: 70% vs M: 67%, P = 0.717, multivariate: P = 0.657), age (>60 y.o.) (L: 50% vs M: 44%, P = 0.665, multivariate: P = 0.061), interval from collapse to ROSC (≤30 min.) (L: 88% vs M: 64%, P = 0.022, multivariate: P = 0.007), and interval from collapse to ROSC (>30 min.) (L: 21% vs M: 29%, P = 0.567, multivariate: P = 0.449).

Conclusions:
The PCAS victims within 30 min. from collapse to ROSC, would be treated by TH with less than 34°C target temperature.
Abstract 16100: Incidence and Morphologic Characteristics of Plaque Erosion in Patients With Acute Myocardial Infarction: A Combined Optical Coherence Tomography and Intravascular Ultrasound Study
Authors: Higuma Takumi , Tsunenari Soeda , Abe Naoki , Yamada Masahiro , Yokoyama Hiroaki , Shibutani Shuji , Jia Haibo , Minami Yoshiyasu , Vergallo Rocco , Lee Hang , Okumura Ken , Jang IK-Kyung
Published: July 2021

Background:
The underlying mechanisms for acute myocardial infarction (AMI) include plaque rupture (PR), plaque erosion (PE), and calcific nodule (CN). Recently, in vivo diagnosis of PE was reported in patients with acute coronary syndromes (ACS) using optical coherence tomography (OCT). However, the true incidence of erosion in patients with AMI remains unknown.

Aim:
The aims of this study were (1) to evaluate the incidence of PR, PE, and CN in patients with AMI during the acute phase and (2) to compare the detailed plaque morphology in all 3 groups using both OCT and intravascular ultrasound (IVUS).

Methods and Results:
In 77 patients with AMI, both OCT and IVUS were performed following manual aspiration thrombectomy. Culprit plaques were classified into PR, PE, and CN using the established OCT criteria. The frequency of PR, PE, and CN were 62.3%, 27.2%, and 6.5%, respectively. PE had significantly lower prevalence of thin-cap fibroatheroma (TCFA), thicker fibrous cap and smaller lipid arc. Compared to PR and PE, CN had greater calcification (Table). On IVUS, plaque eccentricity index was significantly greater in PE compared to the others. PR and PE showed greater plaque burden. The remodeling index was different among these 3 groups. 75.0% of PR had positive remodeling but none in CN. In contrast, CN had higher prevalence of negative remodeling. The prevalence of superficial spotty calcification was higher in PR than the other 2 groups.

Conclusion:
This combined OCT and IVUS study demonstrates that erosion was the underlying mechanism in 27.2% of patients with AMI. In eroded plaques, TCFA was rare and eccentricity index was significantly greater.
Abstract 16148: Possible Implication of Oxidative Stress in Development of Coronary Vascular Lesions in Kawasaki Disease
Authors: Hamaoka Kenji , Yahata Tomoyo , Suzuki Chinatsu , Okamoto-Hamaoka Akiko , Yoshioka Ayako , Nakamura Akihiro , Ikeda Kazuyuki
Published: July 2021

Introduction:
Kawasaki disease (KD) is an acute systemic pan-vasculitis prevalent in infants and consequently causes coronary arterial lesions (CALs). Furthermore, it has been reported that CALs in KD may increase the risk of early-onset and progression of arteriosclerosis. In this study, we evaluated the possible implication of oxidative stress (OS) in morbid state and developing vascular lesions by measuring the balance between oxidative stress and antioxidative activity.

Methods:
Nineteen patients were enrolled to evaluate the dynamics of OS in the acute phase. All patients were treated with IVIG and aspirin. Thirteen patients responded well to IVIG and six did not respond well. Reactive oxygen metabolites (ROM) and biological antioxidant potential (BAP) were measured before (point A), two days (point B) and 1~2 weeks (point C) after IVIG administration, using FREE.

OS balance in the chronic-phase was examined in 42 late-phase KD patients (mean age; 16.5 years-old), who included 16 patients without CAL (group D), eight with transient CAL (group E), and 18 with persistent CALs (group F).

Results:
In the acute phase of KD, OS was enhanced. ROMs in good response group significantly decreased between points A and B, and points B and C (p< 0.05 and p< 0.01, respectively). In poor response group, there was no significant difference in ROM between points A and B. BAP in good response group significantly increased between points A and C (p < 0.01), but not in poor response group. BAP at point A was significantly lower in the poor response group than the good response (p < 0.01).

No statistically significant differences in ROM and BAP were observed in groups D ~ F, but ROM was the lowest in group F. Potential antioxidative activity (BAP/dROMs) was significantly higher in group F compared with those in groups D and E (p< 0.05). In KD patients with CALs, ROM was the lowest in the combined therapy with antiplatelet medicine plus statin and/or warfarin, and AR was the highest.

Conclusions:
In KD, OS was significantly enhanced in acute phase, and changes in ROM and BAP are clinically useful for evaluating and predicting the effects of IVIG therapy. Furthermore, it was suggested that combined treatment of statin or warfarin may increase potential antioxidant activity.
Abstract 16152: Utility of Peak Systolic Velocity Ratio in Asymptomatic Patients With Restenosis After Endovascular Therapy for Femoro-Popliteal Lesion
Authors: Tohoku Shota , Yoshimitsu Soga , Tomoi Yusuke
Published: July 2021

Introduction:
The predictive factor of whether asymptomatic restenosis needs reintervention after initial therapy remains unclear.

Objective:
The aim of this study was to evaluate whether peak systolic velocity ratio (PSVR) is effective to predict target lesion revascularization (TLR) after endovascular therapy (EVT) for femoropopliteal (FP) lesion.

Methods:
From April 2007 to September 2013, 120 restenotic limbs without ischemic symptoms (mean age: 73.1±9.0, men: 75.0%, stent implantation: 57.5%) were selected and analyzed, 73 limbs underwent reintervention. Median follow-up period was 33.7 months (5.1-110.4 months). They were followed by serial duplex ultrasound (DUS). Restenosis was defined as peak systolic velocity (PSV) > 250cm/s or PSVR > 2.4 by using DUS. We divided them into two groups (High PSVR group (PSVR ≧3.63)and low PSVR group (PSVR < 3.63)). The ratio of TLR was compared between two groups by Kaplan-Meier survival curve. We also analyzed the TLR between balloon angioplasty (POBA) alone and stent implantation on initial EVT. Each cut off value of PSVR were 4.19 and 3.63.

Results:
At 1, 3 and 5 years after initial EVT, Freedom from TLR were significantly different between two groups (76.5%, 33.2% and 18.3% vs 90.7%, 75.4%, and 58.0%, p<0.001). Moreover, two groups were significantly different when analyzed about limbs performed POBA (86.9%, 67.0% and 35.7% vs 69.2%, 29.0% and 14.5%, p =0.048 ) and stenting on initial EVT (92.3%, 77.6% and 51.7% vs 83.8%, 35.2% and 12.0%, p < 0.01). After adjustment for use of cilostazol, use of proton pomp inhibitor , chronic total occlusion, history of EVT for aortoiliac disease, PSVR was an independent predictors of TLR.

Conclusions:
PSVR may be a predictive factor of performing reintervention for asymptomatic patient with restenosis after EVT of FP lesion.