bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14927: Everolimus versus Mycophenolate for Cardiac Transplantation
Authors: Aggarwal Saurabh , Gupta Navdeep , Loomba Rohit S , Al-Khafaji Nawfal , Agarwal Anushree , Ismail Imtiaz , Kaushik Manu , Saurav Alok , Alla Venkata , Arora Rohit R
Published: July 2021

The role of everolimus in cardiac transplantation is being increasingly recognized.Multiple studies have been published comparing the use of everolimus and mycophenolate with varying results. We aimed to perform a meta-analysis of the published literature.

We searched Pubmed, EBSCO and Cochrane databases for terms “everolimus”, “mycophenolate”, “heart transplantation”, “cardiac transplantation” and their combinations. All studies in which everolimus was compared to mycophenolate were included. Studies in language other than English were excluded.

Rates of biopsy proven acute rejection (OR 0.82 CI 0.67 to 1.00, p = 0.05), hemodynamically significant rejection (OR 0.76, CI 0.39 to 1.50, p = 0.43)or change in glomerular filtration rate (GFR) (mean difference -1.91, CI -6.90 to 3.08, p = 0.45) were similar between everolimus and mycophenolate groups. Everolimus use was associated with significant reduction in average maximal intimal thickness (mean difference -0.04 CI -0.06 to -0.02, p = 0.001) and cytomegalovirus antigenemia (OR 0.38, CI 0.28 to 0.53, p < 0.00001). There was no significant heterogeneity for any endpoint except change in GFR.

As compared to mycophenolate, everolimus use is associated with similar antirejection outcomes after cardiac transplantation but with reduced maximal intimal thickness and cytomegalovirus antigenemia.
Abstract 15027: Previous Therapy with Statins Reduces the Inflammatory Response in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Cornara Stefano , Somaschini Alberto , Camporotondo Rita , Crimi Gabriele , Baldo Andrea , Repetto Alessandra , Pavesi Claudia , Pica Silvia , Gnecchi Massimiliano , De Ferrari Gaetano M
Published: July 2021

Background:
Statins are known to possess anti-inflammatory properties in addition to their lipid lowering activity. Several inflammatory biomarkers including leukocyte (WBC) and neutrophil (Neutro) count and neutrophil to lymphocyte ratio (NLR) have been suggested as prognostic markers in patients with ST-elevation myocardial infarction (STEMI).

Aim:
Goal of this study was to investigate whether a previous therapy with statins influenced the inflammatory response of patients with STEMI.

Methods:
Consecutive patients undergoing primary percutaneous coronary intervention (pPCI) for STEMI in our Department from 2006 to 2012 (n=1271) were evaluated. We compared patients on statins at the time of STEMI (103; 8,1%) with the others. Inflammatory indexes were obtained by blood samples collected at hospital admission (T0) and the following day (T1).

Results:
Patients with previous statin-therapy were older (65 ± 12 vs 62 ± 13 years , p=0.007), had more frequently a previous MI (55% vs 8%, p<0.001), hypertension (66% vs 52%, p=0.002), dyslipidemia (75% vs 35% p<0.001), diabetes (25% vs 14%, p=0.002) and familiarity for cardiovascular diseases (44% vs 39%, p=0.01). They also showed a lower LV ejection fraction after PCI (42 ± 10% vs 45 ± 10% p=0.01) The inflammatory response in the two groups is shown in the Table.

Previous statin-therapy was an independent predictor of all inflammatory markers at multivariable analysis.

Conclusions:
Previous statin-therapy at the time of STEMI reduces the inflammatory response, an effect associated with a better prognosis. Thus, treatment with statins in patients at risk not only reduces the incidence of MI but is likely to improve prognosis if a STEMI does occur.
Abstract 15037: Novel Role of Kelch-like ECH-associated Protein 1/NF-E2-related Factor 2 System in Vascular Smooth Muscle Cell Apoptosis Following Vascular Injury
Authors: Ashino Takashi , Yamamoto Masayuki , Numazawa Satoshi
Published: July 2021

Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after vascular injury are a key event in the neointimal hyperplasia followed by vascular occlusive diseases. To maintain vascular functions, the number of VSMCs is tightly controlled by those proliferation and apoptosis during vascular remodeling. Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system plays a critical role in the oxidative stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 function is abrogated in response to oxidative stress, leading to Nrf2 stabilization and coordinated up-regulation of antioxidant genes. We have previously found that Nrf2 plays an important role in neointimal hyperplasia after vascular injury via regulating platelet-derived growth factor-induced reactive oxygen species-dependent VSMC migration; however, the role of Keap1-Nrf2 system in VSMC apoptosis has not been established. Here we show that TUNEL-positive cells are detected in both the layers of neointima and media, both of which observe alpha-smooth muscle actin positive and high Nrf2-expressed cells, 14 days after transluminal arterial injury in mice. Nrf2 deficient mice show decreased TUNEL-positive cells in neointimal and medial areas (60%) and enhanced neointimal formation (I/M ratio: 152%) 14 days after vascular injury compared with the wild-type mice. In VSMCs isolated from the thoracic aorta of rats, depletion of Keap1 with siRNA increases nuclear Nrf2 (685%) and induces its target genes, including NAD(P)H: quinone oxidoreductase-1 (664%) and heme oxygenase-1 (230%). Functionally, Keap1 depletion increase apoptotic morphological features such as cell shrinkage and nuclear condensation (4114%), annexin V binding (512%), and positive TUNEL staining in VSMCs, which is associated with caspase-3/7 activation (576%). Pretransfection of VSMCs with Nrf2 siRNA inhibits apotosis mediated by Keap1 siRNA. In summary, Keap1-Nrf2 system regulates VSMC apoptosis in the process of neointimal formation, thereby inhibiting VSMC hyperproliferation, which may contribute to the development of neointimal hyperplasia after vascular injury.
Abstract 15089: Relationship between Paradoxical Decrease in High-Density Lipoprotein Cholesterol Levels Following Statin Therapy and Severe Cardiovascular Event in Patients with Acute Myocardial Infarction
Authors: Ota Tomoyuki , Ishii Hideki , Suzuki Susumu , Tanaka Akihito , Osugi Naohiro , Kawamura Yoshihiro , Shibata Yohei , Tatami Yosuke , Maeda Kengo , Kondo Takahisa , Murohara Toyoaki
Published: July 2021

Introduction:
Low levels of high-density lipoprotein-cholesterol (HDL-C) are well known as an important risk factor for cardiovascular disease. In addition to lowering low-density lipoprotein-cholesterol (LDL-C), statin therapy increase HDL-C moderately. Contrary to this expectation, we sometimes have experience to paradoxical decrease in HDL-C following statin therapy. The purpose of our study was to analyze the relation between the paradoxical HDL-C decrease following statin therapy and adverse cardiovascular event in patients with acute myocardial infarction (AMI).

Methods:
Total of 724 AMI patients who started statins newly after initial coronary intervention were analyzed. Change in HDL-C levels (ΔHDL) was calculated as HDL-C levels at follow-up coronary angiography minus baseline HDL-C levels. These patients were divided into two groups according toΔHDL; 620 patients with ΔHDL≥0 (increase HDL group) and 104 patients with ΔHDL<0 (decrease HDL group). Severe cardiovascular events were defined as all cause death, myocardial infarction and stroke.

Results:
Change in lipid profile and clinical outcomes were shown in table. Event-free survival curves for severe cardiovascular events appeared in figure. Multivariate analysis showed that decrease HDL and reperfusion time per hour were the independent predictor of severe cardiovascular event (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.106 - 4.132 and HR: 1.070; 95% CI: 1.026 - 1.117, respectively).

Conclusions:
Paradoxical decrease in serum HDL-C levels following statin therapy might be an independent predictor of long-term severe cardiovascular disease in patients with AMI.
Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats
Authors: Ichimura Kenzo , Matoba Tetsuya , Nagahama Ryoji , Nakano Kaku , Sunagawa Kenji , Egashira Kensuke
Published: July 2021

Background:
Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT).

Methods and Results:
Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier).

Conclusion:
A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.
Abstract 15175: Critical Role of Sodium-Glucose Cotransporter 1 in the Cardioprotection Through the Maintenance of Energy Production During Ischemia-Reperfusion Injury
Authors: Kashiwagi Yusuke , Nagoshi Tomohisa , Yoshino Takuya , Anzawa Ryuko , Yoshimura Michihiro
Published: July 2021

Glucose becomes an important preferential substrate for cardiac metabolism and ATP generation under specific pathological conditions, such as ischemia. Glucose utilization is initiated by glucose uptake, which is mainly controlled by glucose transporters. Although the role of passive glucose transporters (GLUTs) has been investigated intensively, little is known about the functional significance of the other active transporter, sodium-glucose cotransporter 1 (SGLT1), in the heart. We herein hypothesized that cardiac SGLT1 plays a critical role for cardioprotection during ischemia-reperfusion injury (IRI), possibly through the enhanced glucose utilization for the energy production. To test this, we studied the effects of 10-4 M of phlorizin, SGLT1 inhibitor, on the baseline function and its response to global ischemia (20 minutes)-reperfusion (40 minutes) injury in mouse Langendorff perfusion model, where SGLT1, but not SGLT2, is highly expressed, as confirmed by immunoblotting assay. Although phlorizin did not affect baseline function, its administration during IRI significantly impaired recovery in left ventricular contraction (% recovery of baseline; 67.3±4.5 vs. 89.7±6.8%, n=5 each, P<0.05) and rate pressure product (18600±1290 vs. 25100±1010 mmHg•bpm, n=5 each, P<0.01), associated with increased infarct size demonstrated by TTC staining as well as CPK activity released into the perfusate (20.8±9.5 vs. 2.0±0.6 U•g, n≥3, P<0.05). Of note, the onset of ischemic contracture, which is thought to be initiated by ATP depletion in cardiomyocytes, was earlier with phlorizin perfusion (288±21 vs. 364±27 sec, n≥8, P<0.05). Consistent with this, the significant reduction of tissue ATP content was observed in phlorizin perfused heart (4.81±0.61 vs. 6.87±0.13 μmol/g tissue, n≥4, P<0.05). In conclusion, these data demonstrate that SGLT1 represents an important cardioprotective mechanism against IRI possibly through the maintenance of ATP generation. Our findings shed new light on the essential role of SGLT1 for the optimization of cardiac energy metabolism by the enhanced glucose availability during ischemia, thus leading to substantial myocardial protection after severe ischemic insults.
Abstract 15183: Do Two Scoring Systems of Coronary Stenosis, Syntax Score and Gensini Score, Similarly Predict Clinical Outcome After Pci in Patients With Stable Angina Pectoris?
Authors: Murakami Naoto , Kokubu Nobuaki , Nishida Junichi , Hase Mamoru , Fujito Takefumi , Kawamukai Mina , Mochizuki Atsushi , Kouzu Hidemichi , Muranaka Atsuko , Shimoshige Shinya , Yuda Satoshi , Hashimoto Akiyoshi , Tsuchihashi Kazufumi , Miura Tetsuji
Published: July 2021

Background:
Few studies have examined if two score systems of coronary stenosis, SYNTAX score and Gensini score, are different as predictors of prognosis in patients with coronary artery disease (CAD). Here we examined this issue in patients with stable CAD after percutaneous coronary intervention (PCI).

Methods:
We retrospectively analyzed 795 consecutive patients who underwent coronary angiography for suspected stable CAD from January 2007 to August 2012. One hundred fifty-nine patients received PCI according to consensus of the Heart Team in our institute and patients’ consents. Overall severity of coronary stenosis and complexity in each patient was quantified by both the SYNTAX score and Gensini score, and patients were divided into high score group and low score group by the mean of the score in overall patients. Follow-up period was 15.9 ± 14.4 months, and MACE was defined as a composite of cardiac death, myocardial infarction, target vessel revascularization and/or congestive heart failure.

Results:
The mean SYNTAX score and Gensini score were 19.0 ± 12.4 and 47.8 ± 26.9, respectively. Long-term MACE in a group with high SYNTAX score (≧19, n=71) tended to be higher than a group with low SYNTAX score (<19, n=78), but not significant (Figure 1). However, long-term MACE was significantly higher in a group with high Gensini score (≧48, n=62) than that in a group with low Gensini score (<48, n=97) (Figure 2). In receiver operating characteristic curve analysis, optimal cut-off value of Gensini score to predict MACE was 66.5, of which sensitivity and specificity were 41.2% and 85.6%, respectively (area under curve 0.63, p=0.008).

Conclusion:
Gensini score is not inferior to SYNTAX in prediction of the clinical outcome after PCI in patients with stable CAD. Prognosis after PCI is favorable in patients with low Gensini score (especially those with GS<66.5).
Abstract 15209: Effects of Coffee Consumption on Exercise Tolerance, Blood Pressure, Heart Rate, Heart Rate Variability and Premature Beats in Volunteers with Coronary Artery Disease
Authors: Mioto Bruno M , Moretti Miguel A , Tarasoutchi Daniela , Amato Reynaldo V , Giorgi Dante M , Grupi César J , Machado César Luiz A
Published: July 2021

Introduction:
Coffee is supposed to increase blood pressure (BP) and heart rate (HR), which may be deleterious for patients with coronary artery disease (CAD). However a review of the literature reveals few studies evaluating these effects in patients with CAD.

Objective:
The aim of this study was to compare the effects of dark roast (DR) and medium dark roast (MDR) paper-filtered coffee on BP, exercise tolerance, HR, heart rate variability (HRV) and extrasystoles in volunteers with CAD.

Methods:
This randomized crossed-over trial compared the effects of consuming three or four cups (150 mL) of DR and MDR coffee per day for 4 weeks in 40 volunteers with CAD. In the baseline and after each 4 weeks period of drinking they were submitted to treadmill test, ambulatory blood pressure monitoring (24-h ABPM) and 24-h Holter ECG. We analyzed average systolic BP (SBP) and diastolic BP (DBP) at 24-h ABPM, total exercise time ([[Unable to Display Character: ∆]]T Exercise) and double product (DP) at treadmill test, and average HR, SDNN, ventricular (VPB) and supraventricular premature beats (SPB) at 24-h Holter ECG. Variables were evaluated by ANOVA for repeated measures and Friedman test when indicated.

Results:
We evaluated 40 subjects with CAD, 64.7 ± 6.7 years old, 32 men. All volunteers received adequate treatment for CAD according to the guidelines. Compared with baseline, subjects had an increase of 6.4% and 5.7% in [[Unable to Display Character: ∆]]T exercise at treadmill test after MDR and DR consumption respectively [565.8 ± 194.8 vs 601.8 ± 212.9 vs 597.8 ± 208.0 s (p=0.001)] without an increase in DP (p=0.91). In the 24-h Holter ECG at baseline, DR and MDR the following values were obtained, respectively: HR [67.1 ± 8.6 vs 66.5 ± 8.2 vs 67.2 ± 8.5 (p=0.71)], SDNN [130.6 ± 32.7 vs 134.2 ± 30.6 vs 129.7 ± 28.5 (p=0.428)], VPB [8.0 (2.0-395.5) vs 9.5 (0.2-54.7) vs 11.5 (3.0-51.7) (p=0.16)] and SPB [18.0 (5.2-73.0) vs 20.0 (5.5-75.5) vs 16.5 (6.2-72.5) (p=0.52)]. In the 24-h ABPM at baseline, DR and MDR the following values were obtained, respectively: SBP [110.8 ± 9.1 vs 109.2 ± 19.9 vs 114.7 ± 11.8 mmHg (p=0.10)] and DBP [64.1 ± 9.1 vs 64.6 ± 9.3 vs 66.4 ± 9.7 mmHg (p=0.14)].

Conclusions:
Paper-filtered coffee increased exercise tolerance and had no considerable effect on BP, HR, HRV and premature beats in volunteers with CAD.
Abstract 15228: Hyperleptinemia Exacerbates High Fat Diet-mediated Atrial Remodeling and Fibrillation
Authors: Ebata Yuki , Fukui Akira , Kondo Hidekazu , Saito Shotaro , Abe Ichitaro , Aoki Kohei , Shinohara Tetsuji , Teshima Yasushi , Saikawa Tetsunori , Takahashi Naohiko
Published: July 2021

Introduction:
Obesity is an independent risk factor of atrial fibrillation (AF). Although serum leptin levels have been reportedly up-regulated in subjects

with obesity and metabolic syndrome (leptin resistance), the relation of hyperleptinemia and AF remains to be solved.

Hypothesis:
We tested the hypothesis whether hyperleptinemia could exacerbate high-fat-diet (HFD)-mediated AF.

Methods:
Eight-week-old male C57BL/6 (WT) and leptin-deficient ob/ob mice (Ob) were treated either with normal-fat-diet (NFD) or 60% HFD. Eight weeks later, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed. The effect of leptin antagonist (LAnt) was also examined using osmotic mini-pump in WT-HFD mice.

Results:
1) HFD increased body weight and plasma leptin concentration in WT mice (both p<0.01). 2) Masson trichrome staining revealed that heterogeneous interstitial LA fibrosis was evident in WT-HFD, which was not observed in Ob-HFD (p<0.05). Up-regulation of collagen1, α-SMA, TNF-α, and MCP-1 mRNA levels observed in WT-HFD mice LA, was attenuated in Ob-HFD mice. 3) While transesophageal burst pacing invariably induced AF (8/8, 100%) in WT-HFD mice, it induced AF less frequently (1/8, 12.5%) in Ob-HFD mice (p<0.01). 4) In isolated perfused heart experiments, interatrial conduction time was prolonged in WT-HFD mice, but not in Ob-HFD mice (p<0.05). 5) Western immunoblotting revealed up-regulated expressions of phosphorylated-calmodulin kinase II (p-CamKII) and Na+-Ca2+ exchanger in WT-HFD mice (both p<0.01). However, these changes were attenuated in Ob-HFD mice. 6) LAnt treatment for 4 weeks attenuated the AF inducibility assessed by transesophageal burst pacing (8/8 vs 2/8, p<0.05).

Conclusions:
Our findings suggest that hyperleptinemia (leptin resistance) plays an essential role in HFD-mediated atrial remodeling and AF. Inhibition of leptin or leptin signaling may become a novel therapeutic target to prevent obesity-related AF.
Abstract 15265: Exome-wide Association Study of the Human Metabolome in a Community-based Cohort
Authors: Rhee Eugene , Yang Qiong , Liu Xuan , Ho Jennifer , Cheng Susan , Clish Clary , Levy Daniel , Ramachandran Vasan , Wang Thomas , O’Donnell Christopher , Gerszten Robert
Published: July 2021

Introduction:
Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We hypothesize that the study of low frequency and rare variants of potential functional significance will refine our understanding of the genetic determinants of human metabolism.

Methods:
We analyzed the association between 217 plasma metabolites and exome variants captured on the Illumina HumanExome Beadchip in 2,076 Framingham Heart Study (FHS) participants. Of the >240,000 variants on the exome array, we restricted our analysis to the subset of 92,633 variants that were polymorphic and nonsynonymous, nonsense, or located in a splice site. We performed association analyses that relate each single variant to each metabolite, as well as gene-based burden tests that evaluate the aggregate effects of all variants within a gene. Statistical analyses accounted for number of SNPs or genes (for burden tests).

Results:
We identified a total of 15 gene-metabolite associations, nine from single variant analysis (
gene
: metabolite):
CTH
(Cystathionine);
BPIFA2
(Betaine);
OR1F1
(Creatinine);
TCF19
(Glycerol);
GMPS
(Xanthosine);
SIGLEC6
(Creatine);
ANKUB1
(Carnosine);
KIAA1751
(Serotonin);
MAP1A
(TAG 58:6). (Bonferroni-adjusted significance threshold of
P
< 5.4 x 10
-7
for all). All but the ANKUB1findings are attributable to rare variants with MAF 0.01 or less. We identified six additional associations from burden tests, including three at established human disease loci:
HAL
(histidine);
PAH
(phenylalananine);
UPB1
(ureidopropionate);
TG
(indole propionate);
CDH5
(SM 22:1);
PHLDB1
(LPE 18:0) (Bonferroni-adjusted significance threshold of
P
< 3.9 x10
-6
for all).

Conclusion:
Our findings highlight genes with a direct biochemical relationship with the given metabolite as well as unanticipated genetic effectors of select metabolites. We show how an examination of variants across the spectrum of allele frequency is able to identify independent association signals at select loci as well as generate a more integrated view of genetic determinants of metabolites.
Abstract 15284: Characteristics and Determinants of Cerebral Circulation in Patients after Surgery for Congenital Heart Disease
Authors: Saiki Hirofumi , Kuwata Seiko , Kurishima Clara , Iwamoto Yoichi , Ishido Hirotaka , Masutani Satoshi , Senzaki Hideaki
Published: July 2021

Background:
Neurodevelopmental delay and cerebral atrophy coupled with reduced blood flow are reportedly closely linked in patients with congenital heart diseases (CHD). However, the mechanisms to regulate cerebral flow in the same are unclear. Cardiac output and underlying cerebral arterial resistance that is constructed during infancy may affect blood perfusion. We tested our hypothesis that cerebral blood flow in patients with repaired CHD is affected by the original features of CHD.

Method:
Ninety children including 50 patients with biventricular repaired CHD (ToF 27, TGA 15, CoA+VSD 8), 15 with a single ventricle (SV: Glenn7/Fontan8) and 25 with negligible shunts and otherwise normal stracture heart were enrolled. During cardiac catheterization, cardiac index (CI), blood pressure, central venous pressure were measured before and after inferior vena cava occlusion. Assuming that cerebral resistance (Rc) and lower body resistance (Ri) are constant during IVC occlusion, the resistance and blood distribution to the brain and lower body were calculated as a parallel resistance circuit. The impacts of hemodynamics on the cerebral circulation were analyzed.

Result:
The cerebral portion of cardiac index (CIc) was negatively correlated with age (CIc=1.88-0.06*Age, p<.05) and positively correlated with the CI (CIc=0.26+0.35*CI, p<.0001). As expected, the cerebral resistance (Rc) increased significantly with age (p<.05), whereas the resistance ratio defined as the Rc/Ri was independent of age, body size, disease, and surgical history. Multivariate analysis revealed that the CI was the independent determinant of CIc, regardless of the underlying diseases (p<.01, β=0.27). Interestingly, after adjusting for age and CI, repaired CoA exhibited significantly higher Rs/Ri ratio (p<.01) and lower CIc (p<.05) than other groups, whereas SV patients showed significantly increased CIc, CIc/CI ratio and lower Rc compared to other groups (p<.05).

Conclusion:
Apart from the strong governance of cerebral blood flow by cardiac output, cardiovascular property before anatomical repair and cavo-pulmonary connections have a significant impact on the cerebral circulation. Long-term effects of abnormal cerebral circulation warrants further studies.
Abstract 15294: Activation of Mac-1 Integrin Prevents G-CSF Mediated Monocyte Mobilization and Atherosclerosis Severity in Hypercholesterolemic Mice
Authors: Rahimpour Sina , Mesa Annia , Song Lei , Fernandez Natasha , Pham Si M , Gupta Vineet , Vazquez Roberto
Published: July 2021

Background:
Leukadherins (LA) are a novel family of Mac-1 agonists that increase cell adhesion and prevent leukocyte mobilization and tissue inflammation. This study brings new insights into how leukadherin LA1 protects hypercholesterolemic ApoE-null mice from excessive atherosclerosis development.

Hypothesis:
Activation of Mac-1 integrin with leukadherin LA1 retains monocytes in medullary and extramedullary centers and therefore, controls high fat diet induced monocytosis and atherosclerosis in ApoE-null mice.

Methods and Results:
Once daily administration of LA1 (10mg/kg) for 16 weeks significantly reduced atherosclerosis in the entire aorta and the aortic valve of high fat diet fed ApoE-null mice as determined by Sudan IV staining. The LA1 treatment had not effect on body weight or plasma lipid levels though it significantly reduced the number of circulating monocytes (Lin2- CD11c- CD11b+ by FACS). The remaining circulating monocytes in LA1-treated mice displayed low levels of Ly6C, a marker for inflammation. Interestingly, LA1 caused monocyte retention in the bone marrow (BM) and macrophages (F4/80+ by IHC) in the spleen of hypercholesterolemic mice, which account for the low numbers of monocytes seem in the circulation of these mice. On the other hand, the excessive number of BM monocytes didn’t compromise the number of hematopoietic (Lin- Sca+ c-Kit+) or myeloid (Lin- Sca- c-Kit+) progenitor cells. Finally, we assessed the effect of LA1 on systemic inflammatory mediators using multiplex immunoassay. The plasma levels of G-CSF, one of the main monocyte mobilization cytokines capable of promoting atherosclerosis in ApoE-null mice, were found reduced in a half in treated versus control mice.

Conclusions:
These data demonstrate that Mac-1 activation with LA1 significantly reduces atherosclerosis in hypercholesterolemic ApoE-null by impairing G-CSF mediated monocyte mobilization from medullary and extramedullary centers.
Abstract 15308: SPARC Deletion Suppresses Age-related Cardiac Inflammation
Authors: Toba Hiroe , de Castro Brás Lisandra E , Baicu Catalin F , Zile Michael R , Lindsey Merry L , Bradshaw Amy D
Published: July 2021

Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein that facilitates the formation and assembly of mature cross-linked collagen fibrils. We previously reported that aged mice exhibit increased SPARC levels in the heart, and SPARC deletion inhibits age-related collagen deposition. The present study investigated whether SPARC deletion could suppress age-related cardiac inflammation. Six groups of mice were studied: young (3-5 month old), middle-aged (10-12 m.o.) and old (18-29 m.o.) C57BL/6J wild type (WT) and SPARC-null (Null) mice (n=5-10 per group). Echocardiography and histology revealed that LV wall thickness and myocyte size were 15% and 43% increased with age in WT, respectively (both p<0.05 old versus young). These age-dependent structural changes were blunted in the Null. The pro-inflammatory chemokines Ccl5 and Ccr2 were increased in middle-aged and old WT, and Cxcl1 was increased in old WT, compared to young WT (all p<0.05). Interestingly, the age-dependent increases in Ccl5, Ccr2, and Cxcl1 were delayed in Null. Migration inhibitory factor (Mif) and Cx3cl1 showed an age-dependent increase in both WT and Null. Cxcl5 expression levels increased age-dependently only in Null, suggesting a compensatory increase for the decline of other chemokines. In summary, these results suggest that SPARC deletion slowed age-related cardiac inflammation.
Abstract 15359: Cost-effectiveness of Different Strategies for the Diagnosis of Stable Coronary Artery Disease: Results from the Evinci Study
Authors: Turchetti Giuseppe , Lorenzoni Valentina , Bellelli Stefania , Pierotti Francesca , Rovai Daniele , Caselli Chiara , Underwood Stephan R , Knuuti Juhani , Neglia Danilo ,   The EVINCI Investigators
Published: July 2021

Introduction:
In patients with suspected coronary artery disease (CAD) the comparative value of non invasive diagnostic imaging modalities or strategies is not yet defined.

Hypothesis:
We hypothesized that a comparative cost-effectiveness (CE) analysis of different non-invasive imaging strategies in a European population of patients with stable angina could identify the best approach for the diagnosis of significant CAD.

Methods:
In 475 pts (291 males, 60±9 yrs) with stable angina enrolled in the EVINCI multicenter study, CT coronary angiography (CTCA) and stress imaging were performed before invasive coronary angiography (ICA). Significant CAD was defined as >50% stenosis in the left main or >70% stenosis in a major coronary vessel or 30-70% stenosis with fractional flow reserve ≤0.8. Non-invasive imaging strategies included CTCA or stress imaging (ECHO, CMR, SPECT or PET) alone or in combination. Combinations were positive if both CTCA and the stress test were positive. CE analysis was performed using per patient data. Effectiveness was defined as percentage of correct diagnosis. Costs were calculated by country-specific reimbursements for each test considered plus ICA costs when non invasive tests were positive. Incremental cost-effectiveness ratios (ICERs) were obtained by regression analysis and using a propensity-score adjustment.

Results:
Significant CAD was diagnosed at ICA in 140 pts (29%). CTCA had the highest diagnostic performance among single imaging modalities and CTCA-PET among combinations (Table). At CE analysis, ECHO approach was the least costly but also the least effective, while CTCA alone or in combination with PET had increasingly higher effectiveness for a willingness to pay (WTP) exceeding 2,000 Euro and 5,000 Euro, respectively (Table).

Conclusion:
Stress ECHO is a cost-effective approach to diagnose stable CAD when the WTP is low. CTCA alone or combined with stress PET allows a more effective diagnostic workflow for higher WTP.
Abstract 15438: Serum Proprotein Convertase Subtilisin/Kexin Type 9 Levels Are Not Increased by Plant Stanol Ester Consumption
Authors: Simonen Piia , Stenman Ulf-Håkan , Gylling Helena
Published: July 2021

Introduction:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating cholesterol metabolism mainly by binding to LDL receptors targeting them for degradation. Statins, inhibitors of cholesterol synthesis, increase the serum PCSK9 concentration limiting the potential of statins to reduce LDL cholesterol (C) concentration, whereas ezetimibe, an inhibitor of cholesterol absorption, has ambiguous effects on circulating PCSK9 levels. Plant stanols lower LDL-C by inhibiting cholesterol absorption, but their effect on serum PCSK9 concentration is not known.

Hypothesis:
We assessed the hypothesis that consumption of plant stanol esters lowers LDL-C without increasing circulating PCSK9 levels.

Methods:
Ninety-two normo- and mildly hypercholesterolemic subjects, 35 men and 57 women (mean age 50.8±1.0 (SE) years) were randomly divided into plant stanol ester (STANOL) (n=46) and control (n=46) groups. They consumed spread enriched with (STANOL group) and without (control group) plant stanol (3g /d) ester in a double-blind intervention for six months. Serum lipids and lipoproteins were analysed enzymatically and serum PCSK9 concentration was quantitated with Quantikine Elisa Immunoassay at baseline and after the intervention.

Results:
At baseline, serum PCSK9 levels correlated positively with LDL-C in the whole study population. Serum total, LDL-C and non-HDL-C concentrations, similar between the study groups at baseline, declined by 7%,10%, and 11% at the end of the intervention in the STANOL group compared with the control group (p< 0.001, for all). The baseline serum PCSK9 concentrations were similar between the groups (STANOL 284±16 ng/ml, controls 273±16 ng/ml, ns). At the end of the intervention, serum PCSK9 concentrations were unchanged from baseline in both groups and did not differ between the groups (STANOL 293 ±15 ng/ml, controls 309±16 ng/ml, ns).

Conclusion:
In conclusion, plant stanol ester consumption does not affect the circulating PCSK9 concentration. Thus, plant stanols provide an efficient dietary means to lower LDL-C concentration without interfering with the LDL receptor-mediated cellular cholesterol uptake and removal.
Abstract 15458: Prevalence and Burden of Abdominal Aortic Plaque Are Inversely Associated With Kidney Function: the Framingham Heart Study
Authors: Chuang Michael L , Gona Philimon , Oyama-Manabe Noriko , Roseman Daniel A , McMahon Gearóid M , Salton Carol J , O’Donnell Christopher J , Fox Caroline S , Manning Warren J
Published: July 2021

Background:
We sought to determine whether renal function as assessed by estimated glomerular filtration rate (eGFR) is independently associated with atherosclerotic abdominal aortic plaque (AAP).

Methods:
1726 adults (65±9y, 53% women) from the Framingham Offspring cohort underwent cardiovascular magnetic resonance (CMR) abdominal imaging (axial T2W black-blood); prevalence and volume of AAP were quantified. Serum creatinine was measured at the adjacent cycle visit and eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equations. We determined prevalence and volume of AAP by sex-specific quartiles of eGFR and tested for trend (Cochrane-Armitage) across quartiles. Multivariable-adjusted logistic regression models were used to determine odds of AAP per 10 units of eGFR.

Results:
For the entire group, eGFR was 84±18 ml/min/1.73m2 and did not differ between sexes. AAP prevalence decreased with increasing eGFR quartile in both sexes (Figure, top): p for trend <0.0001 in men, p=0.0006 in women. Considering only study participants with AAP>0, mean volume of AAP decreased (Figure, bottom) with greater eGFR quartile in both sexes, p<0.0001 for men, p=0.004 for women. Trends remained significant when all study participants (including those with AAP=0) were analyzed. On logistic regression analyses every 10 units of eGFR decreased odds for prevalent AAP by 0.90 (95% confidence intervals 0.84 - 0.97) after adjustment for age, sex and traditional cardiovascular disease (CVD) risk factors; in the same model greater age (OR=1.28 per 10y; 1.10 - 1.48), smoking (OR=1.80; 1.24 - 2.62), and cholesterol treatment (OR=1.50; 1.12 - 2.02) were also associated with greater prevalence of AAP.

Conclusion:
Prevalence and burden of AAP both increase with decreasing eGFR in a community dwelling cohort of adults. Greater eGFR is independently associated with decreased prevalence of CMR-detected AAP even after adjustment for traditional CVD risk factors.
Abstract 15460: Pulmonary Hypertension is Associated with Apoptosis, the Downregulation of S100A1, the Upregulation of S100A6 and the Receptor for Advanced Glycation end-Products
Authors: Tsoporis James , Salpeas Vassilios , Kavatzas Nikos , Izhar Shehla , Desjardins Jean-Francois , Teichert-Kuliszewska Krystyna , Rizos Ioannis K , Parker Thomas G
Published: July 2021

Pulmonary arterial hypertension (PH), defined by a resting mean pulmonary artery pressure (PAP) >25 mm Hg, is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, leading to right ventricular (RV) hypertrophy, failure, and death. Development of PH involves the complex interactions of multiple cell effectors. The possibility that the S100 calcium binding proteins S100A1, S100A6 and their receptor the receptor for advanced glycation end-products (RAGE) may be involved PH and associated apoptosis has not been tested. We examined the levels of S100A1, S100A6, S100B, RAGE and parameters of apoptosis the anti-apoptotic Bcl2 and the pro-apoptotic Bax and terminal deoxynucleotidyl transferase dUTP nick end labelling assay (TUNEL) positive nuclei in lung biopsies negative for malignancy taken by video-assisted thorascopic surgery in 6 control patients (4 male, 2 female) mean age 59.8±4.4 (SEM) years with PA>60 mmHg. S100A1 mRNA and protein as quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and histological evaluation respectively is decreased 50-60%, whereas RAGE and S100A6 mRNA and protein is increased in the whole lung predominantly in PA endothelial and smooth muscle cells approximately 4-10 fold in PH patients compared to controls. Lung S100B levels did not differ between the control and PH groups. The PH group showed a 2.1-3.5 fold increase in the whole lung BAX/BCL2 mRNA ratio and TUNEL positive nuclei compared to controls. Compared to wild type (WT), 10-12 week old S100A1-knockout mice (KO) exhibited an increased right ventricular weight as quantified by the Fulton index (WT-0.24+0.01 vs. KO-0.28+0.01, p<0.05, n=6/group), an elevation in right ventricular systolic pressures (WT-15.5+3.8 vs. KO-28.8+4.6 mmHg, p<0.05) in the absence of altered left ventricular filling pressures, a 1.5-fold increase in lung caspase-3 activity as a marker of apoptosis and 2-3 fold increase in whole lung RAGE and S100A6 mRNA expression. Our data demonstrating that absence of S100A1 results in PH describes a novel murine model of PH, which displays many of the hallmarks of the human disease, thus makes it an attractive therapeutic target in the treatment of PH.
Abstract 15473: The Use of Coronary Artery Bypass Grafts in Non-significant Lesions: Is There Harm to Patients?
Authors: Englum Brian R , Schulte Philip J , Gulack Brian C , Gibson C M , Lopes Renato D , Mack Michael J , Ferguson T B , Harrington Robert A , Smith Peter K , Alexander John H
Published: July 2021

Introduction:
Studies have shown the negative impact of percutaneous coronary interventions in non-flow limiting lesions; however, similar effects have not been examined in the use of coronary artery bypass grafting.

Methods:
Using data from the PREVENT IV trial, we assessed rates of graft failure (≥75%) and adjusted long-term clinical outcomes by degree of native vessel stenosis (> or ≤75%) at the time of CABG. Degree of native vessel stenosis was based on available categories in the PREVENT IV database. Differences in graft failure rates were assessed using the Cochran-Armitage trend test, while clinical outcomes were compared in a multivariable Cox proportional hazards model.

Results:
Of 3,008 patients (including 10,298 grafts), 1,622 (54%) had one or more non-significant lesions bypassed. The use of bypass grafting varied by vessel and degree of stenosis - 95% of non-significant LAD lesions were bypassed, while 86% and 75% of non-significant left circumflex and right coronary artery lesions were bypassed, respectively. In the angiographic cohort (n=1,828 patients and 6,047 grafts), degree of stenosis was not associated with vein graft failure but was associated with internal mammary artery graft failure (Table). The bypass of a non-significant lesion was not associated with death or the composite of death, MI, or revascularization.

Conclusion:
The use bypass grafting to non-significant coronary lesions is common and is associated with higher degrees of IMA graft failure. We did not observe a relationship between bypassing of non-significant lesions and vein graft failure or clinical outcomes but had limited power to do so. Additional observational studies and adequate randomized clinical trials are necessary to define the optimal approach to surgical coronary revascularization.
Abstract 15496: Combined Effect of an Interleukin-6 Gene Variant and Smoking on Endothelial Function, Inflammatory and Thrombotic Processes and Prevalence of Coronary Artery Disease
Authors: Hatzis George , Papageorgiou Nikolaos , Oikonomou Evangelos , Miliou Antigoni , Siasos Gerasimos , Papaioannou Spyridon , Papaoikonomou Stavroula , Toutouzas Konstantinos , Antoniades Charalambos , Stefanadis Christodoulos , Tousoulis Dimitris
Published: July 2021

Introduction:
Smoking is a well known risk factor for coronary artery disease (CAD). Moreover, controversial data suggest that the -174 G/C polymorphism on Interleukin-6 (IL-6) gene promoter (rs1800795) may represent an early marker of inflammatory activation, closely related to the initiation and evolution of atherosclerosis. However, no data exist concerning a combined effect of smoking and this IL-6 genetic variant on several aspects of inflammation and thrombosis, endothelial function and the presence of CAD.

Methods:
646 subjects (361 non smokers) were subjected to appropriate genotyping. Endothelial function was assessed by the flow mediated dilatation (FMD) of brachial artery. IL-6 (pg/ml), Tumor Necrosis Factor-a (TNF-a) (pg/ml), high sensitivity CRP (hsCRP) (mg/l) and D-dimers (μg/l) were measured with appropriate methods.

Results:
An increased incidence of CAD was found among the carriers of the allele C, compared to GG homozygotes, (OR:1.59, CI:1.26-2.93, p=0.032) in smokers, while a decreased incidence was observed in non smokers (OR:0.42, CI:0.26-0.68, p<0.001), after adjustment for all risk factors for CAD. The C allele carriers, compared to GG homozygotes, were associated with significantly higher serum levels of IL-6 (3.09±1.4 vs 1.3±0.7), TNF-a (5.3±2.4 vs 2.57±1.8), hsCRP (2.09±0.9 vs 1.05±0.69) in smokers as well as in non smokers (IL-6: 2.62±1.2 vs 1.64±0.89, TNF-a: 3.57±1.67 vs 4.43±2.1, hsCRP: 1.84±0.82 vs 1.62±0.77), p<0.01 for all. Importantly, the C allele, compared to GG homozygotes, enhanced the expression of fibrinogen (488.3±115.1 vs 318.5±61.1 p<0.001) and D-dimers (513±313.4 vs 355.1±218.4, p=0.025) in smokers, while it down-regulated the expression of fibrinogen in non-smokers (351.9±84.5 vs 479.4±126.4, p<0.001). Impressively, the C allele carriers were correlated with significantly impaired endothelial function in the smoking group (3.9±2.7 vs 5.2±3.3, p=0.003), while no effect was observed among non-smokers (4.8±2.9 vs 5.04±2.6, p=0.64).

Conclusions:
The C allele of rs1800795 exerts a synergistic effect on smoking resulting to a significantly increased risk for CAD. This action is mediated by inflammatory and thrombotic mechanisms as well as by the impairment of endothelial function.
Abstract 15514: The Transcatheter Aortic Valve Replacement Experience in Medicare Patients at Trial and Non-Trial Hospitals
Authors: McCarthy Fenton , Groeneveld Peter , Wirtalla Christopher , Kobrin Dale , Desai Nimesh D
Published: July 2021

Introduction:
Transcatheter aortic valve replacement (TAVR) was recently approved by the Food and Drug Administration (FDA) after a large clinical trial and a collaborative technology development process involving professional medical societies, the medical device industry, and the FDA. This study compares risk-adjusted mortality between hospitals with and without clinical trial experience.

Methods:
All Medicare fee-for-service patients undergoing TAVR (n=5003) between January 1, 2011 and November 30, 2012. Kaplan-Meier and risk-adjusted 30-day and 180-day survival were compared between patients undergoing TAVR at 68 clinical trial hospitals (n=3617) versus patients at 140 non-clinical trial hospitals (n=1392).

Results:
The preoperative characteristics of patients at trial versus non-trial hospitals were similar in age and other comorbidities, with only modest differences observed in the prevalence of chronic heart failure (93% trial hospitals, 89% non-trial hospitals, p<0.01) and peripheral vascular disease (80% trial hospitals, 84% non-trial hospitals, p<0.01). There was no significant difference in risk adjusted 30-day mortality (Odds Ratio [OR] 0.88, 95% CI 0.66 - 1.15, p=0.34) or 180 day mortality (OR 0.99 95% CI 0.75 - 1.3, p=0.94). There was also no difference in mortality in the first ten cases performed at non-trial institutions versus subsequent cases (OR 1.08, 95% CI 0.51 - 2.21, p=0.83).

Conclusions:
There were no significant differences in the mortality between clinical trial versus non-clinical trial hospitals. This is an unusual finding compared to other new cardiovascular devices and procedures for which higher mortality has been observed at hospitals that did not participate in the clinical trials that preceded FDA approval. The unique policy and regulatory environment governing TAVR development therefore could serve as a model for future cardiovascular technology development and dissemination.
Abstract 15523: Absence of Chordae Tendineae near Valve Coaptation Leads to Mitral Regurgitation in Lone Atrial Fibrillation
Authors: Itabashi Yuji , Mihara Hirotsugu , Berdejo Javier , Utsunomiya Hiroto , Matsuoka Ken , Shiota Takahiro
Published: July 2021

Introduction:
Mitral annuloplasty is performed to treat mitral valve regurgitation (MR) in lone atrial fibrillation (AF) patients. The mechanisms of the significant MR in lone AF patients are not known well. We assessed the hypothesis that absence of chordae tendineae near the mitral valve (MV) coaptation could lead to the significant functional MR in the lone AF patients.

Methods:
We analyzed 64 patients with a history of AF with greater than 50 % of the left ventricular (LV) ejection fraction, and no organic abnormality of MV. Of these 31 has mild or lesser MR (AF Groups) and 33 has moderate or severe MR (AFMR Group). We also analyzed 33 sinus rhythm patients with normal echocardiographic findings (Sinus Group). Parameters concerning to MV morphology were measured with commercial software. Chordae attaching points (CAPs) nearest from the coaptation line were detected on the anterior mitral leaflet (Figure). Ratio of the length from CAP to coaptation line against that from anterior annulus to coaptation line was calculated as CAP-C/An-C ratio.

Results:
Mitral annular area (P < 0.05), leaflets surface area (P < 0.05), and CAP-C/An-C ratio (P < 0.05) were larger in the AFMR Group as compared with the AF Group (Table). With multivariate analysis, the correlation factor of significant MR in AF patients was increase in the CAP-C/An-C ratio (Odds ratio (per 1 % increase) = 1.70; p <0.05).

Conclusion:
The absence of chordae tendineae near the coaptation line represented by larger CAP-C/An-C ratio is related to the functional MR in AF patients with normal LV function.