bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3385: Role Of Regional Geometric Dyssynchrony By Real-time Three-dimensional Echocardiography As A Determinant Of Functional Mitral Regurgitation In Patients With Acute Myocardial Infarction
Authors: Hung Chung-Lieh , Verma Anil , Shah Rahman , Hou Charles Jia-Yin , Yeh Hung-I , Tsai Cheng-Ho
Published: July 2021

Background:
Functional mitral regurgitation (FMR) after myocardial infarction (MI) is associated with left ventricular (LV) dys-synchrony and increased mortality. However, determinants of FMR severity after acute MI are poorly defined. Our aim was (1) to test whether real-time Three-Dimensional echocardiography (RT-3DE) can provide insights into the mechanism of LV dys-synchrony on MR severity after MI (2) to investigate role of selective regional dys-synchrony index (DI) in prediction of FMR.

Method:
RT-3DE and Doppler echo was performed on 64 consecutive patients (mean age 62.2 ± 12.5 yrs) following acute MI without cardiogenic shock and with narrow QRS complex (< 120 ms). MR Severity was assessed by vena contracta, and MR jet area/LA area. Dyssynchrony index (DI) was derived from the dispersion of time to minimum regional volume for all 16 LV segments. Pearson’s correlation and multiple linear regression analysis were used to identify the relationship between FMR and DI. Different models of LV dys-synchrony including global index and selective ring-defined (basal, middle and apical ring) regional index were all analyzed and compared.

Results:
The mean LVEF was 49.6 ± 11.9% and LV end-diastolic volume (EDV) was 93.1 ± 23.8ml. All regional and global DIs were significantly correlated with FMR even after adjusting for age, LVEF and EDV (table 1

), with mid-wall DI being most strongly associated with MR severity.

Conclusion:
RT-3DE determined mid-wall DI following MI is strongly associated with FMR. Our results suggest that selective geometric ring-defined DI has better FMR severity prediction and may provide specific approaches to the treatment of FMR complicating MI.
Abstract 3393: Expression Patterns of the Cardiac Myofilament Proteins- Analysis of Surgical Myectomy Tissue from Patients with Sarcomeric Hypertrophic Cardiomyopathy
Authors: Theis Jeanne L , Bos J. Martijn , Gersh Bernard J , Ommen Steve R , Ackerman Michael J
Published: July 2021

Background:
Mutations in sarcomeric/myofilament proteins are commonly implicated in hypertrophic cardiomyopathy (HCM). However, the mechanisms underlying disease pathogenesis are not completely understood. Utilizing flash-frozen surgically resected left ventricular (LV) tissue from patients with obstructive HCM, we investigated the effect of sarcomeric HCM on tissue expression of various myofilament proteins.

Methods:
Frozen surgical specimens from 47 patients with HCM who underwent septal myectomy at the Mayo Clinic between 1999 and 2003 were examined. Using PCR, DHPLC, and direct DNA sequencing, all were genotyped for mutations involving the 8 myofilament-encoding genes that currently comprise the clinically available genetic test for sarcomeric HCM. Whole protein lysate was extracted from the frozen myectomy tissues and levels of myosin binding protein C, myosin heavy chain, alpha actin and alpha actinin were analyzed by Western Blot; GAPDH was used as a loading control. Frozen LV tissue derived from normal hearts of accidental death victims served as a reference group.

Results:
Overall, 25/47 (53%) patients had sarcomeric HCM including 13 patients with myosin binding protein C (MYBPC3) mutations and 10 with mutations in the beta myosin heavy chain (MYH7). Compared to normal heart tissue, the expression of myosin heavy chain was up-regulated significantly regardless of the underlying disease-causing genotype (genotype positive = genotype negative). However, there was gene-specific upregulation of myosin binding protein C with marked increases detected in patients with MYH7-HCM. In contrast, normal levels of myosin binding protein C were seen in patients with either MYBPC3-HCM or genotype-negative HCM.

Conclusions:
This is the first study to examine the expression pattern of sarcomeric proteins in a large collection of flash frozen human HCM myectomy tissue. Up-regulated, genotype-specific cardiac tissue expression of myosin binding protein C among patients with MYH7 (beta myosin heavy chain)-HCM suggests a novel compensatory pathway underlying the development of cardiac hypertrophy for one of most common genetic subtypes of HCM.
Abstract 3400: Regeneration of Human Infarcted Heart Muscle in Chronic Coronary Artery Disease after myocardial infarction: Controlled study with Intracoronary Autologous Mononuclear Bone Marrow Cell Transplantation (IACT-Study)
Authors: Koestering Matthias , Zeus Tobias , Brehm Michael , Bartsch Thomas , Schannwell Christina M , Strauer Bodo E
Published: July 2021

Introduction:
Remodeling of the left ventricle (LV) after myocardial infarction (MI) represents a major cause of infarct-related heart failure and death. After acute myocardial infarction transplantation of bone marrow cells (BMCs) leads to regeneration of infarcted zones due to neovascularization and regeneration of myocardium. We investigated cardiac performance of intracoronary transplantation of autologous BMCs in patients with chronic ischemic heart disease, suffered from transmural myocardial infarction.

Methods:
We treated 120 consecutive patients (51±14 years) with chronic myocardial infarction by intracoronary transplantation of autologous bone marrow mononuclear cells (BMCs) and compared them with a consecutive enrolled representative control group (n=45, 53±11 years). Bone marrow was harvested from the hip (~80 ml) and mononuclear cells were identified including CD34+, AC133+ and CD 34−, CD45−, CD14− cells. The median number of mononuclear cells harvested after overnight culture was 104 x 10
6

Results:
After 3 months in the transplantation group, infarct size was reduced from (32±9 to 25±9%) significantly (p<0.001), and global left ventricular ejection fraction (45±9 to 51±10%) significantly (p<0.001); as well as infarction wall movement velocity (1.86 ± 0.72 to 3,12 ± 0.78cm/s) significantly (p<0.001), while in the control group no significant changes were observed during 3 months follow-up in infarct size (29±9 to 28±9%), in left ventricular ejection fraction (48±10 to 50±15%) and in wall movement velocity of infarcted area (1.81 ± 0.76 to 1.92 ± 0.78cm/s). After bone marrow cell transplantation, there was an significantly (p<0.05) improvement of maximum oxygen uptake (VO2max, +12%) and significantly (p<0.05) of regional 18F-Fluor-Desoxy-Glucose (FDG) uptake (PET) into infarcted tissue (+15%).

Conclusions:
These results demonstrate that selective intracoronary transplantation of autologous BMCs may reduce infarct size and improve LV function and myocardial glucose uptake in chronic ischemic heart disease after chronic infarcted myocardium.
Abstract 3402: Improvement of Left Ventricular Regional Function and Reverse Remodeling in Heart Failure Patients Received Cardiac Contractility Modulation Therapy-A Comprehensive Assessment by Real-Time 3D Echocardiogram and Tissue Doppler Imaging
Authors: Chan Yat-sun , Zhang Qing , Fung Jeffrey W , Chan Anna K , Ma Chun-yan , Yu Cheuk-man
Published: July 2021

Introduction:
Cardiac Contractility Modulation (CCM) is a new form of device based therapy for advance heart failure patient even with normal QRS width and therefore not a candidate for cardiac resynchronization therapy. Previous studies showed that CCM improved left ventricular (LV) ejection fraction (EF) and clinical parameters of heart failure patients. However data from comprehensive echocardiographic assessment and structural reverse remodeling is lacking.

Methods:
18 patients (mean age: 56±9 years, 15 males) with NYHA class III heart failure, QRS <120msec and already on optimal medical therapy received CCM. Real-time 3D echocardiography (RT3DE) (IE33, Philips) and tissue Doppler imaging (TDI) (Vivid 7, GE) were performed at baseline and 3 months after CCM.

Results:
LV reverse remodeling with reduction in volumes and gain in EF was observed by RT3DE at 3 months. TDI also showed improvement of regional systolic function resulting in an increase in peak systolic velocity by measuring 12 (Mean Sm-12) or 6 basal (Mean Sm-6) LV segments. LV filling pressure estimated by E/E’ was also favorably reduced (Table

).

Conclusions:
CCM improves both global and regional LV contractility and reduces filling pressure leading to LV reverse remodeling.

Table
Abstract 3407: Atherosclerotic Plaque Imaging using Phase-contrast X-ray Computed Tomography
Authors: Shinohara Masakazu , Yamashita Tomoya , Tawa Hideto , Takeda Masafumi , Sasaki Naoto , Takeuchi Akihisa , Ohigashi Takuji , Shinohara Kunio , Hirata Kenichi , Kawashima Seinosuke , Yokoyama Mitsuhiro , Momose Atsushi
Published: July 2021

Background:

Reliable non-invasive imaging modalities to characterize atherosclerotic plaque components are clinically desirable for detecting unstable coronary plaques, which cause acute coronary syndrome or sudden death. Although recent clinical developments in computed tomography (CT) have enabled the visualization of luminal narrowing and calcified plaques in coronary arteries, the evaluation of non-calcified plaque components remains difficult. Phase-contrast X-ray CT imaging has great potential to reveal the structures inside soft tissues because its sensitivity to light elements is almost 1000 times greater than that of absorption-contrast clinical X-ray imaging. We for the first time examined mouse atherosclerotic plaques using phase-contrast X-ray CT and found promising results.

Methods and Results:

Ex vivo
phase-contrast X-ray CT was performed using a synchrotron radiation source (SPring-8, Japan) to investigate atherosclerotic plaque components in mice. Samples were also histologically analyzed. Phase-contrast X-ray CT at a spatial resolution of 10 –20 μm revealed atherosclerotic plaque components, and thin fibrous caps could be easily detected. The specific mass densities of these components were estimated using dδ (differences in the refractive indexes relative to water). While lipid-rich areas showed low dδ (0.79 ± 0.13 × 10
−8
) and mass density (1.011 ± 0.001 g/ml), the smooth muscle- and collagen-rich areas showed high dδ (4.18 ± 0.10 × 10
−8
and 5.93 ± 0.13 × 10
−8
, respectively) and mass density (1.057 ± 0.001 g/ml and 1.08 ± 0.002 g/ml, respectively). It was rather easy to evaluate or differentiate the atherosclerotic plaque components using this novel phase-contrast X-ray CT imaging. Moreover, the three-dimensional assessment of plaques was possible, and it enabled the imaging of their anatomical information.

Conclusions:

Phase-contrast X-ray CT can estimate the tissue-mass density of atherosclerotic plaques and distinguish the lipid-rich areas from the collagen-rich areas. This is a promising non-invasive technique for the investigation of plaque components and detection of unstable coronary plaques.
Abstract 458: Critical Role of Bone Marrow Nox2-based NADPH Oxidase in Neovascularization in Response to Hindlimb Ischemia: Impact on Endothelial Progenitor Cells Function
Authors: Urao Norifumi , Inomata Hyoe , Kim Ha Won , Mckinney Ronald , Razvi Mazooma , Fukai Tohru , Ushio-Fukai Masuko
Published: July 2021

Bone marrow (BM) is the major reservoir for endothelial progenitor cells (EPCs). Postnatal neovascularization involves not only angiogenesis but also mobilization of EPCs from BM and their recruitment to the ischemic sites. We demonstrated that reactive oxygen species (ROS) derived from Nox2-based NADPH oxidase play an important role in reparative angiogenesis induced by hindlimb ischemia. However, role of Nox2-derived ROS in BM and EPC function in postnatal neovascularization is unknown. Here we show that Nox2 is the most highly expressed Nox enzymes in mouse BM cells (BMCs) and EPCs. Hindlimb ischemia of mice significantly increases Nox2 mRNA expression (2.3-fold) and ROS production (7.2-fold) in BMCs at 3 days after surgery, which is associated with an increase in number of EPC-like c-kit+Flk-1+ cells in peripheral blood (3.9-fold). Nox2-deficient mice show impairment of ischemia-induced flow recovery (68% inhibition) and significant reduction of ROS levels in BM (98% decrease) and EPC mobilization, as assessed by EPC culture assay (76% decrease) and FACS analysis of c-kit+Flk-1+ cells (33% decrease). Transplantation of wild-type (WT)-BM into Nox2-deficient mice rescues the defective neovascularization. Conversely, WT mice transplanted with Nox2-deficient BM show significant decrease of flow recovery (41% decrease) and capillary density (24% decrease) compared to WT-BM transplanted control. Intravenous infusion of WT-BM-mononuclear cells (MNCs), but not Nox2-deficient MNCs, into WT mice at 1 day after hindlimb ischemia significantly promotes neovascularization (37% increase). Infusion of fluorescent dye-labeled WT- and Nox2-deficient BMCs reveals that homing capacity of Nox2-deficient BMCs in ischemic border zone is significantly reduced (52% decrease). In vitro, VEGF-induced EPC migration (48% decrease) and BMCs invasion (68% decrease) are significantly inhibited in Nox2-deficient cells. In conclusion, Nox2-derived ROS in BM play a critical role in mobilization, homing and angiogenic capacity of EPCs, thereby promoting revascularization of ischemic tissue. Thus, NADPH oxidase in BM and EPCs is potential therapeutic targets for ischemic cardiovascular diseases.
Abstract 461: Sildenafil Improves Ischemia-Induced Neovascularization in ApoE-Deficient Mice
Authors: Dussault Sylvie , Ménard Catherine , Michaud Sophie-Elise , Haddad Paola , Groleau Jessika , Turgeon Julie , Rivard Alain
Published: July 2021

Background: Sildenafil is widely used to treat erectile dysfunction. Sildenafil inhibits phospho-diesterase 5 (PDE5), thereby increasing cGMP levels in target tissues. The NO-cGMP pathway has been shown to be essential for angiogenesis, vasculogenesis and postnatal neovascularization. Therefore, here we tested the hypothesis that sildenafil might improve neovascularization following ischemia.

Methods and results: Hypercholesterolemic ApoE−/− mice, which are characterised by reduced neovascularization in response to ischemia, were treated or not with sildenafil (40 mg/kg/day in water) for the whole duration of the study. Sildenafil was well tolerated by ApoE−/− mice and led to a significant increase of plasmatic cGMP levels compared to controls (13.4±1.9 vs. 4.6±2.6 pmol/mL, p<0.05). After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to a significantly faster rate of blood flow recovery, as assessed by Laser Doppler measurement at day 7 after surgery (55.5% increase, p<0.05). We found that sildenafil treatment is associated with an increased activation of angiogenic transduction pathways such as Akt, p44/42 MAPK, and p38 in ischemic muscles (phosphospecific Western blots). Moreover, sildenafil treatment leads to a significant reduction of oxidative stress in ischemic tissues (nitrotyrosine staining). Endothelial progenitor cells (EPCs) have been shown to participate to postnatal neovascularization. We found that ApoE−/− mice treated with sildenafil have a significant increase in the number of bone marrow EPCs (DiI-AcLDL and FITC-Lectin staining) compared to untreated mice (272±18 vs. 187±17 cells per field, p<0.05). Moreover, the adhesion (19.7±2.1 vs. 10.0±1.9 EPCs per field, p<0.05) and the migratory capacity (28.5±1.8 vs. 15.2±1.3 EPCs per field, p<0.0001) of EPCs are significantly improved in ApoE−/− mice treated with sildenafil.

Conclusions: Sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic conditions. The mechanisms involve beneficial effects of sildenafil on angiogenic pathways in ischemic tissues together with an increase in the number and the functional activity of EPCs.
Abstract 3416: Incremental Diagnostic Utility of Contrast-Enhanced MRI (CE-MRI) vs Contrast Echocardiography for Detection of Left Ventricular Thrombus: Morphologic Predictors of Improved Thrombus Detection by CE-MRI in Patients with Systolic Dysfunction
Authors: Krauser Daniel G , Ross Michael , Min James K , Cham Matthew D , Roman Mary J , Hriljac Ingrid , Kizer Jorge R , Kim Han W , Klem Igor , Kim Raymond J , Devereux Richard B , Weinsaft Jonathan W
Published: July 2021

Background
Accurate detection of left ventricular thrombus (LVT) affects clinical management of at risk pts. CE-MRI identifies LVT based on tissue characteristics and has been validated as a highly sensitive technique that improves LVT detection vs non-contrast echo. However prior comparative studies were performed without echo contrast agents, which can improve echo LVT detection. We studied diagnostic performance of contrast (C-ECHO) and non-contrast echo (NC-ECHO) vs a reference of CE-MRI for LVT detection.

Methods
We prospectively enrolled pts with ejection fraction (EF) <50% referred for CE-MRI (1.5 T) to evaluate for LVT. NC-ECHO and C-ECHO (Definity; perflutren lipid microspheres) were performed within 7 (mean 1.2 ± 1.6) days of CE-MRI. Studies were interpreted blinded to results of the other modality. LVT were scored for location, volume and type (mural or intracavitary). EF was measured by cine-MRI planimetry. Cine and CE-MRI were scored via a 17 segment model to quantify wall motion and scar.

Results
80 pts were studied (age 63 ± 13, 90% CAD, NYHA 2.4 ± 0.7). CE-MRI identified LVT in 25 pts (31%). 84% of LVT were apically located; 32% were mural. All LVT were adjacent to myocardial scar. Pts with LVT by CE-MRI had larger transmural scar size (25 vs 16% of LV segments; p = 0.01) but similar EF (30 vs 33%; p = 0.4) and wall motion score index (2.3 vs 2.1; p = 0.4) to those without LVT. C-ECHO had nearly 2 fold higher diagnostic sensitivity (p = 0.02) and improved accuracy (p = 0.02) vs NC-ECHO (table

). However, C-ECHO did not detect 32% of LVT identified by CE-MRI. LVT missed by C-ECHO were more likely to be mural (p < 0.01). Apically located LVT were more likely to be missed when small (0.9 vs 4.1 cm3; p = 0.01) while detection of non-apical LVT was independent of size.

Conclusions
While echo contrast improves diagnostic performance for LVT, a substantial number of LVT identified by CE-MRI are not detected by C-ECHO. LVT missed by C-ECHO are typically mural in shape or, if apical, small in volume.

Left Ventricular Thrombus Detected by CE-MRI (n = 25)
Abstract 3438: Comparison of Endothelial Progenitor Cell Capture Stent with Bare Metal Stent In Patients Undergoing Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction
Authors: Edgar Tay Lik-Wui , Melissa-Co Chua , Chi-Hang Lee , Adrian Low , Jimmy Lim , Ing-Haan Lim , Swee-Guan Teo , Cheem Tan Huay
Published: July 2021

Background:
The endothelial progenitor cell (EPC) capture bio-engineered stent (Genous
®
stent, OrbusNeich) was designed to attract circulating EPCs and promote rapid endothelization. The aim of this study was to compare clinical outcomes between patients with ST-segment elevation myocardial infarction (STEMI) who received this stent versus those who received Liberte (Boston Scientific) bare metal stents.

Methodology:
Three hundred and forty two patients who presented to our centers with STEMI without cardiogenic shock and underwent primary PCI with either EPC Capture-or bare metal stent implantation were enrolled in this study. All patients received dual anti-platelet therapy for a month; and statin therapy was initiated soon after PCI. The study endpoints were major adverse cardiac events (MACE) at 30 days, 6 months and 1 year.

Results:
A total of 164 EPC Capture stents and 178 BMS were implanted. Baseline patient characteristics were comparable in the 2 groups. The mean lesion length in the 2 groups were 20.4.0 ± 5.1 and 22.8 ± 7.6mm, and the mean reference vessel diameter 3.14 ± 0.65 and 2.70 ± 1.14 mm respectively. At 6 months, the results were:

Conclusion:
There was no significant difference in MACE at 6 month between EPC Capture-and bare metal stents in patients with STEMI who underwent primary PCI. The 1-year data will be presented at the meeting.
Abstract 3441: Differential endothelialization of stent struts across side branches: A Scanning Electron Microscopy analysis.
Authors: Zheng Yi , Fernandes Marlos R , Silva Guilherme V , Cardoso Cristiano O , Canales John F , Baimbridge Fred , Oliveira Edie M , Vaughn William , Hansen Maria G , Perin Emerson C
Published: July 2021

Background: The higher incidence of MACE events in paclitaxel eluting stents (PES) has been attributed to the presence of coronary artery side branches (SB) within stented segments. This study aimed to evaluate PES struts overlying SB in a porcine model of coronary restenosis.

Methods: In a balloon overstretch model of coronary restenosis (balloon:artery ratio =1.2:1), 20 animals were randomized to either PES or bare metal stents (BMS). After 30 days, 22 stented segments were analyzed by Low Vacuum Scanning Electron Microscopy (SEM) and endothelialization was assessed using a score (0=100% endothelialization; 1=99 – 67%; 2=66 –34%; 3=33–1%; 4=0%). Comparison of the distribution of endothelialization scores for struts overlying and non-overlying SB was performed within each group by the Fisher exact test.

Results: A total of 18 struts overlying SB (10 PES and 8 BMS) sized from 200 to 1800μ m, were identified by SEM. In the BMS group, complete endothelialization was observed in 62.5% of SB struts and 100% of non-overlying SB struts. In PES only 20% of SB struts, but almost 100% of the non-overlying SB struts were completely endothelialized. The endothelialization of struts overlying SB was significantly different in PES and BMS groups(Fig 1A

and Fig 1B

), with a higher frequency of impaired endothelialization (scores 3 and 4) in PES struts crossing SB.

Conclusions: PES struts overlying SB showed significantly impaired endothelialization compared with BMS in a pig model of coronary restenosis. This results might offer a new insight to explain the higher incidence of adverse events in PES stented segments. Further studies are needed to confirm the present study results.
Abstract 3442: Pattern and Time Path of Neonintimal Healing in Drug Eluting versus Bare Metal Stents in the Rat Aortic Stent Model
Authors: Groenewegen Hendrik C , Roks Anton J , Goris Maaike , Zijlstra Felix , van Gilst Wiek H , de Smet Bart J
Published: July 2021

Purpose:to determine if the neointima of drug-eluting stents is histological different from their bare metal controls. Neointimal formation in stented aortas was evaluated quantatively and qualitatively at two time points.

Methods:male Wistar rats were randomized to one of four groups: Express 2 stent , Taxus Express 2 stent , Bx Velocity stent and Cypher stent. Stents were implanted in the abdominal aorta. Histological analyses were performed after 1 and 4 weeks. After 1 week the inflammation score and neointimal cell density was measured. Stented aortas were also examined for acellularity of neointima and /or the presence of a hemorrhage in the neointima. After 4 weeks the same measurements were performed plus the neointimal area and neointimal thickness.

Results:no differences were observed after 1 week between bare metal stents and drug-eluting stents. At 4 weeks neointimal cell density was lower and inflammation-score was higher in the drug eluting stents. Furthermore in less than 10% of the bare metal stents acellularity of neointima and/or hemorrhage was found. On the contrary, in more than 90% of the drug eluting stents acellularity of neointima and/or hemorrhage was seen. Neointima area and neointimal thickness was reduced in the drug-eluting stents. No histological differences were found between the paclitaxel and the sirolimus eluting stent.

Conclusions:Both drug eluting stents are effective in reducing neointimal formation however in both drug eluting stents acellular areas were observed in the neointima of almost every single stent. This is likely to be a reflection of incomplete healing which persists after neointimal formation has peaked.

Table 1.

Histological measurements: results in the 4 week groups.
Abstract 3451: Reduced Glomerular Filtration Rate Independently Predicts the Diagnosis of Peripheral Arterial Disease and Extent of Coronary Artery Disease
Authors: Wilson Andrew , Beck Kendall , Assimes Themistocles , Balasubramanian Naras , Olin Jeffrey , Cooke John P
Published: July 2021

5Impaired renal function is an important emerging risk factor for atherosclerosis. Whether this is independent of other cardiovascular risk factors is not clearly known. We aimed to assess whether renal impairment was independently associated with the degree of coronary and peripheral atherosclerosis.

Methods and Results
One thousand and sixty seven subjects (mean ± standard deviation; age 66 ± 11 years, 63% male, 51% any history of smoking, 30% history of diabetes) undergoing elective coronary angiography for exertional chest pain and/or dyspnea were studied as part of the NHLBI funded Gene-PAD study. Angiograms were reviewed by an experienced angiographer, blinded to subject details. Significant CAD was defined as an epicardial stenosis of ≥70% in any vessel. PAD was defined as an ankle brachial index <0.9. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease formula. Patients on dialysis or with acute infections, inflammatory and/or malignant disease were excluded. There was a 29% prevalence of PAD in subjects with GFR <60 mL/min/1.73 m
2
and 16% if GFR was >60 mL/min/1.73 m
2
(p <0.001 for difference). There was no difference in glucose, pack years smoking, BMI, lipids or c-reactive protein levels between subjects with GFR above or below 60 mL/min/1.73 m
2
. Reduced GFR was also predictive of a diagnosis of PAD [odds ratio (95%CI) =0.37 (0.17–0.83)}], independent of these other risk factors in logistic regression. Other predictors of PAD were increasing age, pack years smoking, fasting glucose and elevated triglycerides. Using ordinal regression, reduced GFR was an independent predictor of number of diseased coronary vessels (standardized coefficient −0.93, p =0.004). This was independent of age, gender, body mass index (BMI), lipids, blood pressure, pack years smoking and glucose. Other predictors in this model were age, male gender and lower high density lipoprotein cholesterol.

Conclusion
Reduced GFR is associated with PAD and extent of CAD in a high risk group of subjects, independent of other risk factors. The mechanism for this association is unknown but does not appear to be explained simply by an excess of risk factors. Estimating GFR may be of value evaluating patients at highest risk of PAD and multivessel CAD.
Abstract 3456: Assessment of Genetic Risk for Hypertriglyceridemia
Authors: Kato Kimihiko , Oguri Mitsutoshi , Yoshida Tetsuro , Hibino Takeshi , Yajima Kazuhiro , Fujimaki Tetsuo , Yokoi Kiyoshi , Matsuo Hitoshi , Warita Shunichiro , Segawa Tomonori , Watanabe Sachiro , Metoki Norifumi , Yoshida Hidemi , Satoh Kei , Aoyagi Yukitoshi , Yasunaga Akitomo , Park Hyuntae , Tanaka Masashi , Nozawa Yoshinori , Ichihara Sahoko , Yamada Yoshiji
Published: July 2021

Introduction.
Hypertriglyceridemia is an important risk factor for coronary heart disease. The purpose of the present study was to identify gene polymorphisms associated with hypertriglyceridemia (serum triglyceride concentration, ≥1.65 mmol/L) for assessment of the genetic risk for this condition.

Methods.
A total of 5206 individuals from two independent populations was examined: Subject panel A comprised 3787 individuals who either visited outpatient clinics of or were admitted to the participating hospitals because of various symptoms or for a health checkup; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Given the multiple comparisons of genotypes with hypertriglyceridemia, we adopted the criterion of a false discovery rate (FDR) of <0.05 for significant association in initial screening with the chi-square test.

Results.
Evaluation of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that seven polymorphisms [−1131T→ C, −3A→G, and 553G→T (Gly185Cys) of
APOA5
; 1100C→T of
APOC3
; 85T→C of
APOA1
; 41A→G (Glu14Gly) of
ACAT2
; C→G (Ser47Stop) of
LPL
] were significantly (FDR < 0.05) associated with hypertriglyceridemia in subject panel A. To validate these associations, we examined the same polymorphisms in subject panel B. The six polymorphisms of
APOA5
,
APOC3
,
APOA1
, and
LPL
, but not that of
ACAT2
, were again significantly associated with hypertriglyceridemia. Serum triglyceride concentrations differed significantly (
P<
0.05, ANOVA) among genotypes of each of these six polymorphisms in both subject panels. The three polymorphisms of
APOA5
were in linkage disequilibrium.

Conclusions.
Polymorphisms of
APOA5
,
APOC3
,
APOA1
, and
LPL
are determinants of hypertriglyceridemia. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for hypertriglyceridemia and may contribute to the personalized prevention of this condition.
Abstract 3462: The Cardioprotective Effects Of The Angiotensin-converting Enzyme Inhibitor Perindopril In Patients With Stable Coronary Artery Disease Are Not Modified By Mild to Moderate Renal Insufficiency: Results From The Europa-trial.
Authors: Brugts Jan Jasper , Boersma Eric , Chonchol Michel , Deckers Jaap , Remme Willem , Bertrand Michel , Ferrari Roberto , Fox Kim , Simoons Maarten
Published: July 2021

The cardioprotective effects of the ACE-inhibitor perindopril in patients with stable coronary artery disease are not modified by renal function: Results from the EUROPA-trial.

Objective: To examine whether the cardioprotective effects of perindopril are modified by renal function in patients with stable coronary artery disease.

Background: A recent study reported that an impaired renal function identified a subgroup of patients with stable coronary artery disease more likely to benefit of ACE-inhibition therapy. In light of the growing interest in tailored-therapy for targeting medications to specific subgroups, remarks on the consistency of the treatment effect by ACE-inhibitors are highly important.

Methods: The present study involved 12056 patients with stable coronary artery disease without heart failure randomized to perindopril or placebo. Estimated GFR (eGFR) was calculated using the abbreviated MDRD-equation.

Results: Mean eGFR was 76.2 (18.1) ml/min per 1.73 m
2
. During follow-up, the primary endpoint (cardiovascular death, non-fatal myocardial infarction, or resuscitated cardiac arrest) occurred in 454/5761 patients (7.9%) with eGFR ≥ 75 and in 631/6295 patients (10.0%) with eGFR<75. Treatment benefits of perindopril were apparent in both patient groups either with eGFR≥ 75 (HR 0.77; 95%CI 0.64 – 0.93) or eGFR≥ 75 (HR 0.84; 95%CI 0.72– 0.98). We observed no significant interaction between renal function and treatment benefit (Pv=0.47). Using different cut-off points of eGFR at the level of 60 or 90 resulted in similar trends.

Conclusion: The treatment benefit of perindopril is consistent and not modified by the level of renal function.
Abstract 3477: Platelet Hyper-responsiveness in Aspirin-Treated Patients with Clinical Cardiovascular Disease Compared to Matched High Risk Controls
Authors: Faraday Nauder , Yanek Lisa R , Moy Taryn F , Vaidya Dhananjay , Herrera-Galeano J. E , Becker Lewis C , Becker Diane M
Published: July 2021

Background: Platelet hyper-responsiveness to activating stimuli during aspirin (ASA) therapy may discriminate between high risk subjects who have developed acute thrombotic cardiovascular disease (CVD) events (coronary disease and stroke) and those who are at increased risk but are disease free. We hypothesized that subjects with documented CVD would have greater platelet reactivity on ASA therapy compared to matched high risk non-CVD subjects.

Methods: Subjects (N=228; 61 +/− 8 yrs, 69% male, 60% white) were selected from families with known CVD; 114 had prevalent CVD and were matched on age, sex, and race to 114 apparently healthy controls with risk factors but without clinical CVD. CVD risk factors were measured and therapy adherence was determined by questionnaires. Platelet reactivity on 81 mg ASA/day was determined by whole blood (WB) aggregometry, platelet function analyzer (PFA) closure time, thromboxane B2 (TxB2) release
ex vivo
, and urinary excretion of 11-dehyrothromboxane B2 (Tx-M)
in vivo
. Results. CVD cases had greater platelet reactivity by all measures, both unadjusted, and adjusted for age, sex, race and adherence (Table

). Multivariable adjustment for cardiac risk factors and statin therapy eliminated case-control differences for Tx-M, but not for the ex vivo measures of platelet activation. ASA therapy duration in CVD subjects (8.8 +/− 6.2 yrs) was not related to platelet function.

Conclusions: Greater residual platelet reactivity exists during ASA therapy in CVD subjects compared to matched high risk controls, even controlling for CVD risk factors and adherence to therapy. The data suggest that platelet hyper-responsiveness during ASA chemoprophylaxis may differentiate patients with CVD from those who are at risk for CVD, but have not developed it. Platelet hyper-responsiveness may be an intrinsic property of CVD, related to as yet unidentified environmental or genetic factors.
Abstract 469: Altered Plasma vs. Vascular Biopterins In Human Atherosclerosis Reveal Relationships Between Endothelial Nitric Oxide Synthase Coupling, Endothelial Function And Inflammation
Authors: Antoniades Charalambos , Shirodaria Cheerag , Leeson Paul , Crabtree Mark , Pillai Ravi , Ratnatunga Chandi , Tousoulis Dimitris , Stefanadis Christodoulos , Channon Keith M
Published: July 2021

Introduction:
Tetrahydrobiopterin (BH4) is a regulator of endothelial nitric oxide synthase (eNOS) coupling but its synthesis is also stimulated by inflammation in experimental models. We defined for the first time, the relationships between plasma and vascular biopterins in patients with coronary artery disease, and we determined the impact of BH4 on endothelial function, eNOS coupling, and O2- production in human vessels.

Methods
: Paired samples of saphenous veins (SV) and internal mammary arteries (IMA) were obtained from 219 patients undergoing coronary bypass surgery. Vasomotor responses to acetylcholine (Ach) were determined ex-vivo and vascular O2- (± the eNOS inhibitor LNAME) was measured by chemiluminescence. Biopterins were measured by HPLC.

Results:
High vascular BH4 was associated with better vasorelaxations of SV to Ach, whereas high plasma BH4 was associated with worse vasorelaxations (Fig. a-b

). There was an inverse association between plasma and vascular biopterins (Fig c

). High vascular (but not plasma) BH4 was associated with lower O2-and less L-NAME inhibitable O2- (suggesting better eNOS coupling) in both SV and IMA (Fig c

). Finally, serum C-reactive protein was correlated with plasma biopterins (r=0.268, p=0.001) but not with vascular biopterins in SV (r=0.02, p=0.0857) or IMA (r=−0.044, p=0.717).

Conclusions
: There is an inverse association between plasma and vascular biopterins in patients with atherosclerosis. Vascular but not plasma BH4 is a modulator of NO bioavailability and eNOS coupling in human vessels, while plasma total biopterin is rather a marker of systemic inflammation, than a regulator of vascular function in vivo.
Abstract 3498: The Association of Breastfeeding in Infancy and Adult Cardiovascular Disease Risk Factors: The Framingham Third Generation Cohort
Authors: Parikh Nisha I , Hwang Shih-Jen , Ingelsson Erik , Benjamin Emelia J , Fox Caroline S , Vasan Ramachandran S , Murabito Joanne M
Published: July 2021

Background:
Public health recommendations advocate breastfeeding in infancy as a means to reducing later-life obesity. However many prior studies relating breastfeeding to cardiovascular (CVD) risk factors have been limited by lack of adjustment for maternal and participant confounding factors.

Methods:
In 962 Framingham Third Generation participants (mean age = 41 yrs, 54% women) we related history of breastfeeding (yes vs. no) and CVD risk factors in young-mid adulthood. Breastfeeding data was ascertained via questionnaire from mothers enrolled in the Framingham Offspring Study. Dependent variables were body mass index (BMI), HDL-cholesterol (HDL-c), total cholesterol, triglycerides, fasting blood glucose, C-reactive protein (CRP), systolic (SBP) and diastolic blood pressure (DBP). Covariates for multivariable adjustment were age, sex, hypertension medications, lipid treatment, smoking, birth order, oral contraceptives, hormone replacement, physical activity, education, maternal smoking, maternal education, and maternal BMI. Low HDL was defined as < 50 mg/dL (women) and < 40 mg/dL(men). Adiposity categories were defined by BMI normal [< 25], overweight [≥ 25 to < 30] and obese [≥ 30 kg/m
2
]. Generalized estimating equations (GEE) were used to account for sibling correlations.

Results:
Overall 26% of participants were reported by their mother to have been breastfed. Compared to non-breastfed individuals, breastfed offspring had lower adult BMI [adjusted mean 26.1 kg/m
2
vs. 26.9 kg/m
2
, p = 0.04) and higher adult HDL-c levels [adjusted mean HDL 56.6 mg/dL relative to 53.7 mg/dL p = 0.01] in multivariable-adjusted models. Breastfeeding was not associated with other examined adult CVD risk factors. Upon adjustment for BMI the association between breastfeeding and HDL was attenuated (p = 0.09). Breastfeeding was associated with high versus low HDL (multivariable-adjusted OR = 1.55, p = 0.04) but not with overweight or obesity versus normal weight (p = 0.26, 0.13 respectively).

Conclusions:
Breastfeeding in infancy is inversely associated with adult BMI and positively associated with HDL-c. Associations between breastfeeding and BMI appear to mediate most of the association with HDL-c.
Abstract 3511: Quality of Life in COURAGE Trial Patients with Diabetes
Authors: Maron David J , Spertus John A , Kolm Paul G , Sedlis Steven P , Mancini G.B. John , Hartigan Pamela M , Shaw Leslee J , Dada Marcin , Teo Koon K , O’Rourke Robert A , Boden William E , Weintraub William S
Published: July 2021

Background:
The COURAGE trial randomized 2,287 patients to percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) or OMT alone. We hypothesized that patients with diabetes would have lower quality of life (QOL) at baseline and benefit less from PCI than patients without diabetes.

Methods:
Angina frequency and QOL were assessed with the Seattle Angina Questionnaire (SAQ) at baseline, 1, 2, and 3 years. Diabetes and treatment group differences were assessed by analysis of variance and linear mixed effects models.

Results:
(See Table

.) Diabetes status could be determined in 2,234 patients. Of these, 766 (34%) had diabetes. There were no significant baseline differences in SAQ scores for angina frequency and QOL for patients with and without diabetes. All patients experienced significant (p<0.001) improvement in these SAQ scores from baseline through 3 years post-randomization in both treatment arms, however patients without diabetes had significantly greater improvement (p<0.001 for both scores). The addition of PCI to OMT produced a small but statistically significant advantage for patients without diabetes that persisted for 2 years for angina frequency and 1 year for QOL; a similar advantage for PCI was observed for patients with diabetes, but this was not statistically significant, due in part to the smaller sample size. Comparison of SAQ Scores by Diabetes Status and Treatment

Conclusions:
COURAGE patients with and without diabetes had similar baseline angina frequency and QOL, and experienced marked improvement in these parameters in both treatment groups. Diabetic patients had less improvement in these health status scores than non-diabetic patients. The addition of PCI to OMT produced a small incremental benefit compared with OMT alone that lasted for 1–2 years, after which there were no between-group differences for patients with or without diabetes.
Abstract 3512: Disruption of Whole Nitric Oxide Synthase System Causes Impaired Glucose Tolerance and Insulin Resistance in Mice in Vivo
Authors: Nakata Sei , Tsutsui Masato , Shimokawa Hiroaki , Sabanai Ken , Yatera Yasuko , Shibata Kiyoko , Morishita Tsuyoshi , Suda Osamu , Tasaki Hiromi , Nakashima Yasuhide , Yanagihara Nobuyuki , Otsuji Yutaka
Published: July 2021

Background

: Nitric oxide (NO) synthase (NOS) system consists of 3 different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). We have recently succeeded in developing mice lacking all NOS genes (triply n/i/eNOS-KO mice) (
PNAS
2005). Our preliminary study has revealed that the triply-KO mice develop acute myocardial infarction (AMI). The present study was designed to investigate abnormalities of glucose metabolism, an important risk factor of MI, in those mice.

Methods and Results

: Experiments were performed in 3-month-old male wild-type (WT) and triply-KO mice (n=5–7). At 15 minutes after intravenous glucose administration (1 g/kg), plasma glucose levels (mg/dl) were significantly higher in the triply-KO (475 ± 44) than in the WT mice (241 ± 20) (
P<
0.05), and plasma insulin levels (ng/dl) were significantly lower in the triply-KO (0.50 ± 0.03) than in the WT mice (0.78 ± 0.03) (
P<
0.05). In the triply-KO mice, the size of pancreatic islets (islet/pancreatic area, 0.64 ± 0.16 vs. 2.81 ± 0.64%) was significantly smaller (
P<
0.05), and significant apoptosis of pancreatic islets (apoptotic/total islets, 19 ± 2 vs. 3 ± 1%) (TUNEL staining) was noted as compared with the WT mice (
P<
0.05). Furthermore, insulin sensitivity (as assessed by insulin-induced [
3
H]-glucose uptake in isolated soleus muscle) (fold increase) was markedly reduced in the triply-KO mice (1.1 ± 0.03) as compared with the WT mice (2.1 ± 0.3) (
P<
0.05), associated with an impairment of insulin-induced translocation of glucose transporter-4 (GLUT-4) to the cellular membrane (immunofluorescent staining) (
P<
0.05). Importantly, supplementation of NO by long-term treatment with isosorbide dinitrate (0.4 mg/day, 6 weeks, dermal application) significantly reversed all these abnormalities of glucose metabolism in the triply-KO mice; plasma glucose (280 ± 28) and insulin levels (0.89 ± 0.10) after glucose tolerance test, insulin sensitivity (1.5 ± 0.08), and GLUT-4 translocation were all improved (all
P<
0.05).

Conclusions

: These results indicate that disruption of whole NOSs system causes impaired glucose tolerance and insulin resistance in mice in vivo, suggesting a critical role of endogenous NO/NOSs system in maintaining glucose metabolism.
Abstract 3518: High Remnant Lipoprotein Levels Adversely Affect Short- and Long-term Outcomes for Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus
Authors: Nakamura Takamitsu , Hirano Mitsumasa , Kitta Yoshinobu , Kodama Yasushi , Mende Akira , Obata Jun-ei , Kawabata Ken-ichi , Takano Hajime , Kugiyama Kiyotaka
Published: July 2021

Diabetes mellitus (DM) adversely affects prognosis in patients with acute myocardial infarction (AMI). Evidence shows that lipids-lowering therapy rather than glycemic control reduces macrovascular events in these patients, but it remains unclear which lipoprotein fractions contribute to negative effects. We previously showed that high levels of remnant lipoprotein, a triglyceride-rich lipoprotein, were an independent risk of future coronary events in patients with chronic coronary artery disease and DM. This study examined the hypothesis that remnant lipoproteinemia may adversely affect short- and long-term prognosis in patients with AMI and DM.

Methods and Results:
A prospective study was performed in 268 consecutive patients with Type 2 DM who were enrolled on day 5 after AMI. Fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) on day 5 after AMI were measured by an immunoseparation method. Adverse events, a composite of cardiac death, nonfatal MI, or recurrent unstable myocardial ischemia leading to unplanned revascularization therapy, were assessed during follow-up periods of 30 days and 1 year after AMI. Events rates were higher in patients with than without higher RLP-C levels (≥ 5.5 mg/dL, 50
th
percentile of the distribution) during both short- and long-term follow-up periods (30 days post-MI, 8.2% [11/134 patients] vs. 2.2% [3/134 patients], p <0.05; 1 year post-MI, 15% [20] vs. 7.5% [10], p <0.05). In multivariate Cox hazard analyses, higher RLP-C levels were a significant predictor of adverse events during 30 days and 1 year independently of enrollment levels of glucose, LDL-C, and non-HDL-C (hazard ratios 2.1 and 1.7, 95% CI 1.8 – 3.9 and 1.3 – 4.0, respectively, both p<0.01). RLP-C levels were significantly correlated with C-reactive protein levels and intimal thickening of carotid artery at enrollment (r =0.30 and 0.39, respectively, both p<0.01).

Conclusions:
High remnant lipoprotein levels adversely affect short- and long-term outcomes in patients with AMI and Type 2 DM. The pro-inflammatory and pro-atherothrombogenic effects of remnant lipoprotein may contribute to coronary plaques instability in patients with AMI and Type 2 DM.
Abstract 3521: Relationship Between Time from Symptom Onset to Hospital Presentation and Treatment with and Timeliness of Reperfusion Therapy for Patients with ST-Elevation Myocardial Infarction
Authors: Ting Henry H , Bradley Elizabeth H , Wang Yongfei , Nallamothu Brahmajee K , Curtis Jeptha P , Gersh Bernard J , Roger Veronique L , Lichtman Judith H , Krumholz Harlan M
Published: July 2021

Background: Whether patients with STEMI with longer times from symptom onset to hospital presentation are less likely to be treated with any reperfusion therapy or treated with less urgency resulting in longer door-to-balloon and door-to-needle times is not known. The relationship between delay in hospital presentation and the quality of reperfusion therapy for patients with STEMI has not been examined

Methods: We constructed 3 cohorts of STEMI patients to analyze use of any reperfusion (n=440,398), door-to-balloon time (n=67,207), and door-to-drug time (n=183,441) as a function of delay in hospital presentation. We constructed multivariable generalized linear models for each outcome to estimate the associations between delay in hospital presentation adjusted for all patient and hospital characteristics.

Results: In adjusted analysis, longer times from symptom onset to hospital presentation was associated with lower use of any reperfusion therapy (p<0.0001 for trend). For early presenters with times of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, 77%, 77%, and 73% of patients received any reperfusion therapy, respectively, and late presenters with times >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours were treated with any reperfusion therapy in 53%, 50%, and 46%, respectively. Delay in hospital presentation was associated with longer drug-to-balloon and door-to-drug times (p<0.0001 for trend). For time intervals of ≤ 1 hour, >1 to 2 hours, >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, patients with STEMI were treated with door-to-balloon times of 99, 101, 106, 123, 125, and 123 minutes respectively. For delay time intervals of ≤ 1 hour, >1 to 2 hours, >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, patients were treated with door-to-drug times of 32, 34, 36, 46, 44, and 46 minutes, respectively.

Conclusions: Longer time from symptom onset to hospital presentation has important implications for subsequent treatment and was associated with lower use of any reperfusion therapy and longer door-to-balloon and door-to-drug times. Longer delay in hospital presentation is associated with worse system performance for reperfusion therapy quality and represents an opportunity to improve quality of care for STEMI patients.