bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3605: Lipoprotein-Associated Phospholipase A
2
and Myocardial Infarction in Women
Authors: Hatoum Ida J , Nelson Jeanenne J , Rexrode Kathryn , Manson JoAnn , Rimm Eric B
Published: July 2021

Lipoprotein-Associated Phospholipase A
2
(Lp-PLA
2
) is an enzyme that hydrolyzes oxidized phospholipids in low-density lipoprotein, creating pro-inflammatory molecules that are hypothesized to play a role in the development of coronary heart disease. Many of the previous studies that have shown Lp-PLA
2
activity to be associated with a moderate increase in risk for CHD have been conducted mostly among men. The one previous study among women was small and reported a modest nonsignificant increase in risk. Thus, the association of Lp-PLA
2
with CHD risk in women warrants exploration. We conducted a nested case-control study among participants in the Nurses’ Health Study who provided a blood sample in 1989 –1990. With approximately 15 years of follow-up through 2004 we identified 438 incident cases of fatal and non-fatal MI and used incidence density sampling to match controls to cases (2:1) based on age, smoking status, date of blood draw, and fasting status at the time of blood draw. Lp-PLA
2
activity was measured using a colorimetric activity assay. We used conditional logistic regression in multivariate models. Compared to women in the lowest tertile, the relative risk of CHD for women in the second and third tertiles of Lp-PLA
2
activity were 1.75 (95% CI 1.26 –2.44) and 2.67 (1.94 – 3.69), respectively (p for trend = 0.002). After further adjustment for LDL cholesterol, c-reactive protein,body mass index, alcohol intake, aspirin use, physical activity, and post-menopausal hormone use, and histories of hypercholesterolemia, diabetes, and hypertension, the relative risks were similar: 1.81 (1.26 – 2.60) comparing the second to the first tertile, and 2.26 (1.54 – 3.30) comparing the third to the first tertile (p
trend
< 0.001). Further adjustment for HDL cholesterol modestly attenuated the relative risks to 1.62 (1.13 – 2.35) and 1.81 (1.20 – 2.71) (p
trend
= 0.007). The significantly elevated relative risks were not appreciably modified by HDL or LDL. In conclusion, we found that Lp-PLA
2
activity was associated with increased risk for MI among women. Adjustment for standard risk factors modestly attenuated this relationship, but Lp-PLA
2
remained a strong independent predictor of MI in this population of women healthy at baseline.
Abstract 3607: Plasma ω-3 polyunsaturated fatty acids associated with reduced risk of heart failure among women: the Atherosclerosis Risk In Communities (ARIC) Study
Authors: Yamagishi Kazumasa , Nettleton Jennifer A , Folsom Aaron R
Published: July 2021

BACKGROUND
A previous prospective study showed that dietary intakes of fish or ω-3 polyunsaturated fatty acids (PUFA) were associated with reduced risk of heart failure (HF), but no study has examined the association between plasma ω-3 PUFA and HF. Our
a priori
hypothesis was that plasma ω-3 PUFA would be inversely associated with incident HF.

METHODS
We included 3,592 white participants from the Minneapolis field center of the ARIC Study, aged 45– 64 at baseline (1987– 89), initially free of coronary heart disease, stroke and HF. Fractions of plasma cholesterol ester (CE) and phospholipid (PL) ω-3 PUFA of marine origin (eicosapentaenoic acid [EPA], ω-3 docosapentaenoic acid [DPA] and docosahexaenoic acid [DHA]) were measured by gas-liquid chromatography. The subjects were followed through 2003, and incident HF was defined by a hospital discharge or death including a HF ICD code. The hazard ratio and 95% confidence interval (HR [95%CI]) for HF was calculated according to quintiles of CE and PL fractions of ω-3 PUFA.

RESULTS
During the 14.3-year follow-up, we identified 197 cases of CHF (110 for men and 87 for women). After adjustment for age and potential risk factors (smoking, pack-years, alcohol consumption, body mass index, systolic blood pressure, antihypertensive medication use, plasma total cholesterol, diabetes and total energy intake), the incidence of HF for women was associated inversely and linearly with ω-3 PUFA in the PL fraction (HR for highest quintile
vs
lowest quintile was 0.27 [0.12– 0.63], p for trend <0.001). There was a similar tendency for the CE fraction for women (HR=0.45 [0.20 –1.03], p for trend =0.08). No associations were observed for men (interaction for gender p=0.04 for PL fraction).

CONCLUSIONS
We found a significant inverse association between plasma ω-3 PUFA and incident HF among women, consistent with a prior study using a food frequency questionnaire. Contrary to our hypothesis, however, no such association was observed for men.
Abstract 3631: Elevated In-hospital Glucose Level, and not Known History of Diabetes Mellitus, Predicts 30-day Mortality Following Acute ST-elevation Myocardial Infarction
Authors: Goyal Abhinav , Diaz Rafael , Gerstein Hertzel C , Afzal Rizwan , Mehta Shamir R , Xavier Denis , Zhu Jun , Pais Prem , Lisheng Liu , Kazmi Khawar A , Zubaid Mohammad , Piegas Leopoldo S , Widimsky Petr , Yusuf Salim
Published: July 2021

Introduction:
According to clinical risk assessment guidelines, a history of diabetes mellitus (DM) portends poor outcomes following acute MI. Elevated in-hospital glucose levels also predict early mortality in acute MI patients, but the degree to which glucose levels and diabetic history independently predict post-MI mortality is unclear.

Methods and Hypothesis:
We analyzed data from the combined cohort of the CREATE-ECLA and OASIS-6 randomized trials that evaluated the impact of glucose-insulin-potassium (GIK) infusion versus no infusion on 30-day mortality in 22,943 patients hospitalized with acute ST-elevation MI. We calculated the average in-hospital glucose level for each patient (mean of the admission, 6-hour, and 24-hour glucose levels). Logistic regression was performed to determine whether average glucose level and history of DM remained significant mortality predictors after adjusting for age, sex, and GIK allocation.

Results:
Glucose data were recorded in 22,860 (99.6%) patients; 10,050 (44%) had an average in-hospital glucose level ≥ 8 mmol/L (144 mg/dL), of whom 65% did not have known prior DM. Among patients with glucose >8 mmol/L, 30-day mortality rates were similar in patients with and without known DM (Figure

). In-hospital glucose, but not history of DM, was a significant multivariable predictor of mortality (Table).

Conclusions:
By considering only history of DM and not in-hospital glucose levels, risk assessment guidelines for acute MI overlook a large proportion of patients at high risk for early death. Therefore, clinicians should emphasize elevated glucose levels in addition to history of DM as a risk marker in patients with acute MI.
Abstract 3645: Alcohol Volume, Not Drinking Frequency, Increases Plasma High-Density Lipoprotein Sub-Class Particle Concentration
Authors: Harriss Linton R , English Dallas R , Wolfe Rory , Tonkin Andrew M , O’Dea Kerin , Peeters Anna , Beauchamp Alison , Giles Graham G , Otvos James D , Jenkins Alicia J
Published: July 2021

Introduction:
Alcohol intake is positively associated with high-density lipoprotein (HDL) cholesterol, however no studies have investigated the association with lipoprotein sub-classes using nuclear magnetic resonance spectroscopy (NMR).

Hypothesis:
We assessed the hypothesis that usual daily alcohol intake (volume), beverage type and drinking frequency influence plasma HDL sub-class concentrations as determined by NMR.

Methods:
Six hundred and ninety volunteers (389 women) aged 40 – 69 years at baseline (1990 –1994) participated in a cross-sectional study using the Melbourne Collaborative Cohort Study, Australia. Measures included self-reported alcohol intake using beverage-specific quantity-frequency questions (volume) and a drinking diary for previous week (frequency).

Results:
Median alcohol intake was 15.2 g/d (2.7, 32.0) for men and 1.0 g/d (0, 9.6) for women. Alcohol volume was positively associated with total HDL particle concentration in men and women. For men, a 10 g/d increment in alcohol intake increased total HDL particle concentration by 0.62 μmol/L (95% CI: 0.27, 0.98) and small HDL particle concentration by 0.34 μmol/L (0.01, 0.68). For women, total HDL particle concentration increased 1.06 μmol/L (0.60, 1.53) for every 10 g/d increment in alcohol intake. Alcohol volume was positively associated with large HDL particle concentration in premenopausal women [0.67 μmol/L (0.19, 1.15)] and small HDL particle concentration in postmenopausal women [0.82 μmol/L (0.14, 1.51)]. Beer, wine and spirits were all positively associated with total HDL concentration for men. Beer and wine were both positively associated with total HDL concentration for women. Drinking frequency was not associated with total HDL particle concentration or any of its’ sub-classes.

Conclusions:
Alcohol volume (and not drinking frequency) was positively associated with NMR-determined plasma total HDL particle concentration for men and women. These associations appeared to be regardless of beverage type, although comparison of beverage types was not possible for women. These results suggest that for any given weekly volume of alcohol, the number of drinking days does not influence HDL particle concentration.
Abstract 3648: Clinical Cardiovascular Disease in Women is Associated With Increased Epicardial, but Not Subcutaneous Fat Thickness
Authors: Oyama Noriko , Gona Philimon , Chuang Michael L , Jhaveri Rahul R , Salton Carol J , Blease Susan J , Levy Daniel , Manning Anya R , O’Donnell Christopher J , Manning Warren J
Published: July 2021

INTRODUCTION: Visceral adipose tissue, such as epicardial fat, is metabolically active, and may portend increased risk for cardiovascular disease (CVD) compared to subcutaneous fat. Cardiovascular magnetic resonance (CMR) can accurately delineate fat, but data are sparse regarding the relationship of epicardial and subcutaneous fat burden to CVD in community-living adult women.

METHODS: 957 women (aged 64± 8 years) in the Framingham Heart Study Offspring cohort, followed by serial examinations since 1974, underwent CMR on a 1.5-T Philips system using an ECG-gated cine SSFP sequence. Epicardial fat thickness (EFT) over the midlevel right ventricle was measured from a 4-chamber view. Suprasternal subcutaneous fat thickness (SFT) was measured at the main pulmonary artery level. We compared EFT and SFT between women with clinical CVD, documented by a physician endpoint committee (+CVD), vs. those without (noCVD) based on Cycle 7 (1998 –2002) clinical data. Differences were assessed by two-sample T-test; ANOVA was used to adjust for age, diabetes, hypertension and menopausal status.

RESULTS: The +CVD group comprised 74 (8%) women who were older and more likely to be postmenopausal, diabetic and hypertensive than noCVD women (Table

). EFT was greater in +CVD (10.5 ± 5.1mm) vs. noCVD (8.6 ± 5.2mm) groups, p<0.003. This difference remained significant after adjusting for age, diabetes, hypertension and menopausal status (Table

). No difference in SFT or body mass index was observed between groups (p=NS).

CONCLUSIONS: Women with history of clinical CVD have greater EFT than women without CVD, and this difference persists after adjustment for common cardiovascular risk factors. However, subcutaneous fat, as assessed by chest wall adiposity, did not differ between groups. EFT may be a useful marker for cardiovascular risk, and prospective investigation of the relationship between EFT and future risk for CVD is warranted.
Abstract 3649: Menstrual Cycling and Mechanisms of Cardiovascular Disease Events in Post-Menopausal Women: Results from the NIH-NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE)
Authors: Johnson B. Delia , Merz C. Noel Bairey , Azziz Ricardo , Braunstein Glenn D , Shaw Leslee J , Pepine Carl J , Sopko George , Kelsey Sheryl F
Published: July 2021

Background:
Menstrual cycling irregularity is being associated with greater frequency of diabetes and adverse cardiovascular (CV) events, suggesting a mechanistic link between ovarian dysfunction, CAD risk factors, and CAD. Confirmation of this link and potential explanatory mechanism(s) have not been established.

Methods:
We compared 686 postmenopausal women with and without a history of irregular cycles who were undergoing coronary angiography for suspected ischemia and enrolled in the WISE study. Coronary angiography was assessed by a core laboratory, and the women were prospectively followed for a median of 5.9 years. Chi square and rank sums analyses were used to compare the women on the presence and severity of CAD, CAD risk factors, and CV events. Multivariate Cox regression, adjusting for angiographic CAD and CAD risk factors was used to define time to death, MI, stroke, and angina hospitalization.

Results:
Overall mean age was 62, 18% were non-white, 130 (19%) reported a history of irregular cycles, and 42% had CAD (≥ 50% stenosis). Women with irregular cycles were younger (p=0.01) but did not exhibit more diabetes, obesity, or metabolic syndrome than those with regular cycles. They became menopausal at a younger age (42 ±10 vs 46 ±8, p=0.001) and had more frequent hysterectomy or oophorectomy (both p<0.01). Women with irregular cycles had a similar adjusted prevalence and severity of angiographic CAD compared to those without irregular cycles, yet had a doubled risk for MI (6% vs. 3%, p=0.02) and higher angina hospitalization rate (34% vs. 28%, p=0.01). No differences were found for the incidence of stroke or death. The relationship was maintained in risk-adjusted models controlling for metabolic syndrome, ethnicity and angiographic CAD severity (p=0.01 for MI and p=0.01 for angina hospitalization).

Conclusion:
Although less commonly applied, a history of menstrual cycling irregularity may be an important clinical marker of downstream risk, which is not immediately explained by the presence or severity of CAD risk factors or angiographic CAD. Additional, non-CAD risk factors, such as hormonal, inflammatory and thrombotic variables, may play a role mechanistically in the link between menstrual irregularity and adverse events.
Abstract 488: Sinoatrial Nodal Pacemaker Cells (SANC) Exhibit High Basal CA Activated Adenylyl Cyclase (AC) Activity and Express Multiple Distinctly Localized AC Types
Authors: Graham David R , Younes Antoine , Lyashkov Alexey , Sheydina Anna , Volkova Maria , Mitsak Megan , Vinogradova Tatiana , Ruknudin Abdul , Boheler Kenneth , Van Eyk Jennifer , Lakatta Edward
Published: July 2021

In SANC constituitive AC generates high basal cAMP, inducing PKA-dependent phosphorylation that regulates Ca2+ cycling, that is essential for normal pacemaker function. Our goals were to identify, in rabbit SANC, the types of AC expressed, and their Ca2+ sensitivity and location. Radioimmunoassay (with total phosphodiasterase inhibition) showed a high Ca2+ activated basal AC activity. AC activity increased 5-fold from Ca2+ free (EGTA) to 1 uM free Ca2+. RT PCR (using specifically designed rabbit primers) showed that AC types II and V, and Ca2+ activated types, I and VIII, are expressed in SANC. The organization of these distinct AC types within calveolar or non-calveolar membrane microdomains was determined in pooled SANC isolated from 5 hearts, using triton x100, and sucrose gradient ultracentrifugation. Lipid domains segregated into caveolin containing and non-caveolin containing membrane microdomains, where AC activity was concentrated (fig

, AC activity). Immunoblots demonstrated localization of different AC types between these two membrane domains, with AC I, II, V/VI localizing to caveolin containing lipid rafts, and AC VIII present in both caveolin and GM1 lipid domains, and also in the soluble fraction (fig

). In summary, multiple ACs, both Ca2+ activated and non-CA2+ activated types, are expressed in SANC, and these reside in distinct calveolar and non-calveolar lipid domains. We conclude that constituitive basal AC activity is, generated, in part, at least, by a Ca2+ activated AC. type.
Abstract 3705: Risk factors and Clinical Outcomes for Contrast Induced Nephropathy Post Percutaneous Coronary Intervention in Patients with Normal baseline Renal Function
Authors: Chong Eric , Shen Liang , Chan Yiong H , Tan Huay C
Published: July 2021

Background:
Contrast induced nephropathy (CIN) is an important complication post percutaneous coronary intervention (PCI). We examine the risk factors for developing CIN in patients with normal baseline renal function so that prophylactic measures may be undertaken to prevent its development.

Methods:
A cohort of 5086 patients with normal baseline renal function (defined as serum creatinine <1.5mg/dl) who did not receive prophylactic treatment while undergoing PCI (primary or elective) between May 1996 to March 2007 in our centre was enrolled in the study. We examine the occurrence of CIN (defined as >25% increase from baseline creatinine within 48 hours post PCI) in 3036 subjects of this cohort with available creatinine data and aim to identify the clinical predictors.

Results:
CIN occurred in 7.3% of the patients. The mean age of these patients was 57.5 yrs, 78.7% were men, and 34.6% had diabetes mellitus. Clinical predictors for CIN were age (OR 6.4, 95% CI 0.1–13.3, p=0.042), female gender (OR 2.0, 95% CI 1.5–2.7, p=0.001), lower left ventricular ejection fraction (OR 1.02, 95% CI 1.01–1.04, p=0.01), anemia with hemoglobin <11mg/dl (OR 1.5 (95% CI 1.01–2.4, p=0.044) and systolic hypotension with blood pressure <100mmHg on admission(OR 1.5, 95% CI 1.01–2.2, p=0.004). While there was no increase in the incidence of CIN among diabetics and nondiabetics (8.2% vs 6.8%, p=0.18), those who are on insulin therapy are at the highest risk compared with diabetics on diet control and oral hypoglycemic drugs (18.9% vs 3.6% vs 6.8%, p=0.001). There was no significant difference between patients who underwent primary vs elective PCI (7.0% vs. 6.6% p=0.75). Patients who developed CIN had higher mortality rate at 1 month (14.5% vs 1.1%, p<0.001) and 6 month (17.8% vs 2.2%, p<0.001)

Conclusion:
Patients with normal baseline renal function undergoing PCI are also at risk of developing CIN with resultant higher mortality. Age, female, insulin dependent diabetes mellitus, hypotension, anemia, low left ventricular ejection fraction are predictors of CIN. Such patients should also be considered CIN prophylactic therapy.
Abstract 3719: Using the Framingham Risk Score to Select Low-risk Men for CAC Screening
Authors: Taylor Allen J , Feuerstein Irwin M , Wu Holly , Bindeman Jody , Bauer Kelly , Byrd Carole , O’Malley Patrick G
Published: July 2021

Background
Although coronary artery calcium (CAC) is predictive of future CHD, screening for CAC in low risk populations is controversial. Criteria are needed to narrow the screening population to those in whom CAC measurement is most efficient (vs. unselected screening). In this analysis, we report the relationship between CAC and CHD outcomes across Framingham risk score (FRS) subgroups to test whether there is a differential relationship between CAC and outcomes across baseline risk.

Methods
In 1634 unselected male volunteers (mean age 42, mean 10 year CHD FRS 4.6%, CAC prevalence 22.4%), we evaluated the independent relationship between CAC and incident CHD over 5.6 years including hard events (hospitalized unstable angina, myocardial infarction and CHD death) and coronary revascularization. The cohort was stratified into tertiles of FRS to explore the relationship between CAC and CHD outcomes.

Results
FRS tertile cutpoints were 0 –3%, 3–5%, and >5% 10 year CHD risk. Over a mean 5.6 years ± 1.5 year of follow-up (range: 1.0 to 8.3 years), there were 22 total CHD events, including 14 hard events and 8 revascularizations. The majority of events occurred in the highest FRS tertile (n = 14), versus the middle (n= 6) and lowest risk tertiles (n=2; P = 0.005). Only in the highest FRS tertile was there a significant relationship between CAC and CHD outcomes.

Conclusion
Among asymptomatic low risk men, the presence of CAC demonstrates substantial discriminating power in predicting events, but appears to be most clinically useful when the 10-year FRS exceeds approximately 5%. If screening with CAC is pursued among low risk men, it should be preceded by a FRS and restricted to those with scores >5%.
Abstract 3720: External Validation of Established Risk Adjustment Models for Procedural Complications after Percutaneous Coronary Intervention on an Independent Data Set
Authors: Kunadian Babu , Das Raj , Dunning Joel , Vijayalakshmi Kunadian , Sutton Andrew G , Muir Douglas F , Wright Robert A , Hall James A , de Belder Mark A
Published: July 2021

We sought to validate the two risk adjustment models (Mayo Clinic,US & NWQIP,UK models) for in-hospital PCI complications on an independent data set of patients undergoing PCI.

Methods:
Between September 2002 and August 2006, 5034 consecutive PCI procedures (Validation set) were performed on a patient group characterized by a high incidence of AMI (16.1%) and cardiogenic shock (1.7%). Two external models of in-hospital complications (in-hospital death; Q-wave MI; emergent CABG; and CVA) after PCI, one developed by the North West Quality Improvement Programme (NWQIP; n = 9914) and the other by the Mayo Clinic (MC; n = 5463), were externally validated.

Results:
In this patient group, an overall in-hospital complication rate of 2% was observed. Multivariate regression analysis identified risk factors for in-hospital complications that were similar to the risk factors identified by the two external models. When fitted to the data set, both external models had an area under the ROC curve ≥ 0.85 (c index (95% CI), NWQIP; 0.86 (0.82, 0.9), MC; 0.87(0.84, 0.9)) indicating overall excellent model discrimination and calibration (Hosmer-Lemeshow test, p > 0.1). The NWQIP model was accurate in predicting in-hospital complications in different patient subgroups.

Conclusions
We have externally validated both models. Despite differences in variable selection, these predictive models yield comparable results when applied to patient groups in a different geographic population other than the one on which the original model was developed. These prediction rules can be useful for risk-adjustment analysis and for prognostication for individual patients.
Abstract 3744: Cystatin C Is Associated With Mitral Annular Calcification In Elderly Adults: Results From The Cardiovascular Health Study
Authors: Asselbergs Folkert W , Mozaffarian Dariush , Katz Ronit , Kestenbaum Bryan , Fried Linda F , Gottdiener John S , Shlipak Michael G , Siscovick David S
Published: July 2021

Background
: A high prevalence of cardiac calcification has been observed in patients with end-stage kidney disease. The association between cardiac calcification and milder kidney disease has been less thoroughly characterized. We hypothesize that renal function is associated with mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) in elderly.

Methods and results
: From the
Cardiovascular Health Study
(CHS), we analyzed 3,929 subjects (74 ± 5 years, 60% women), who underwent a 2-dimensional echocardiogram between 1994 –1995. Measures of kidney function were creatinine-based estimated glomerular filtration rate (eGFR) as calculated by the MDRD equation and cystatin C levels. MAC was present in 42 %, AAC in 44%, and AVS in 54% of the subjects. Subjects with MAC, AAC, and AVS were significantly older and significantly more subjects used anti-hypertensive medication and had prevalent cardiovascular disease (p<0.05). Participants with MAC had higher blood pressure levels, LDL-cholesterol levels, waist to hip ratio, fibrinogen levels and a higher prevalence of diabetes (p<0.05). Participants with AVS were more likely to be male, had higher systolic blood pressure, lower HDL-cholesterol, and higher waist to hip ratio (p<0.05). Levels of cystatin C were significantly higher in subjects with MAC in comparison to subjects without MAC (mean ± standard deviation 1.12 ± 0.33 versus 1.07 ± 0.25 mg/L, p<0.001). We found similar differences in those with and without AAC (1.11 ± 0.33 versus 1.07 ± 0.25 mg/L, p<0.001). Using logistic regression analysis, there was a significant and graded association between quartiles of Cystatin C levels and MAC (adjusted odds ratios and 95% confidence intervals) 1.0, 1.09 (0.91 to 1.32), 1.16 (0.96 to 1.40), and 1.27 (1.04 to 1.55) for quartiles 1 through 4 respectively (p for trend 0.017). In addition, Cystatin C levels were significantly associated with AAC (p<0.001), but this association became non-significant after adjustment for co-variates (p<0.174). No associations were present between Cystatin C and aortic sclerosis, and eGFR and cardiac calcifications.

Conclusion
: Cystatin C was significantly associated with the presence of MAC in a population-based cohort of elderly.
Abstract 3749: Chronic Kidney Disease and Risk for Premature Cardiovascular Disease
Authors: McCullough Peter A , Li Suying , Collins Alan J , Chen Shu-Cheng , Jurkovitz Claudine T , Norris Keith C , McFarlane Samy , Johnson Bruce , Shlipak Michael , Obialo Chamberlain , Brown Wendy W , Vassaloti Joseph , Bakris George L
Published: July 2021

Background
. Chronic kidney disease is recognized as an independent cardiovascular disease risk state, particularly in the elderly, and has been defined by levels of estimated glomerular filtration rate (eGFR) and markers of kidney damage. The relationship between the presence of chronic kidney disease (CKD) and premature cardiovascular disease (CVD) has not been previously described.

Methods.
Volunteers at risk for chronic kidney disease completed surveys regarding past medical events and underwent blood pressure, and laboratory testing. Estimated GFR was computed using a 4-variable equation and the urine albumin:creatinine ratio (ACR) was measured. Data were stratified by decile of age. Premature CVD was defined as a myocardial infarction (MI) or stroke < age 55 years in men and <65 years in women. Mortality was ascertained by linkage to national data systems.

Results.
Of 34,614 the mean age was 46.5 γ 11.5 years, 68.5% were female, 36.2% African American, and 23.0% had diabetes. A total of 21.5% were found to have CKD (defined as eGFR < 60 ml/min/1.73 m2 and or ACR >= 30 mg/g), with the ACR and eGFR being the dominant positive screening tests for CKD in the younger and older age deciles, respectively, p<0.0001 for both trends. The composite rates of premature MI, stroke, or death for those with and without CKD were 8.0 and 3.9%, p < 0.0001. Multivariate analysis found CKD, OR = 1.43, 95% CI 1.26 –1.61; hypertension OR = 1.65, 95% CI 1.43–1.89; diabetes, OR = 1.94, 95% CI 1.72–2.19; smoking, OR 1.87, 95% CI 1.62 – 2.15; female gender, OR=1.64, 95% CI 1.45–1.87; and less than high school education, OR=1.56, 95% CI 1.35–1.82, as the most significant predictors of premature CVD or death (all p <0.0001). Survival analysis found those with premature MI or stroke and CKD had the poorest short term survival over the next three years after screening, p<0.0001.

Conclusions:
Chronic kidney disease is an independent predictor of premature MI, stroke, and death. These data suggest the biologic changes that occur with CKD promote CVD at an accelerated rate that cannot be fully explained by conventional risk factors. Screening for CKD by using both the ACR and eGFR can identify individuals at high risk for premature CVD and near term death.
Abstract 3758: High Pulse Wave Velocity has a Strong Impact on Early Carotid Atherosclerosis in a Japanese General Population
Authors: Kubozono Takuro , Miyata Masaaki , Hamasaki Shuichi , Saito Kazuto , Kusano Ken , Kubozono Osamu , Tei Chuwa
Published: July 2021

Background
: Pathological changes in large arteries make an important contribution to the pathogenesis of cardiovascular disease. The etiology and progression of such changes involve both structural and functional components. Intima-media thickness (IMT) of carotid artery has been reported to be associated with cardiovascular mortality and morbidity. Pulse wave velocity (PWV), which reflects functional arterial stiffness, is reported to be a prognostic predictor of cardiovascular disease. The purpose of this study is to investigate the association between carotid IMT and cardiovascular risk factors in a Japanese general population.

Methods
: The study group consisted of 1843 subjects (1583 men, 260 women, mean age: 57±10 years) undergoing routine health checkups. IMT of common carotid artery was measured with high-resolution ultrasonography. Brachial-ankle (baPWV) and blood pressure (BP) was measured using automated device. Obesity was shown by body mass index ≥ 25.0 kg/m2. Hypertension was defined as systolic BP (SBP) ≥130 mmHg or diastolic BP (DBP) ≥ 85 mmHg. Dyslipidemia was identified by low density lipoprotein cholesterol (LDL) concentration ≥ 140mg/dl, triglyceride (TG) ≥ 150 mg/dl, or high density lipoprotein cholesterol (HDL) ≥ 40 mg/dl. Impaired fasting glucose (IFG) was defined as fasting glucose ≥ 110 gm/dl.

Results
: Univariate analysis demonstrated that carotid IMT significantly associated with age, BMI, SBP, DBP, baPWV, fasting glucose, LDL, TG, and HDL. Multiple logistic regression analysis for carotid atherosclerosis (carotid IMT ≥ 1.0 mm) was performed using obesity, hypertension, dyslipidemia, IFG, and high baPWV (≥ 400 cm/sec). After adjustment for age and gender, carotid atherosclerosis was significantly associated with high baPWV (OR: 2.256, 95% CI: 1.244 – 4.093, P < 0.01) and hypertension (OR: 1.543, 95% CI: 1.009 –2.361, P < 0.05).

Conclusion
: Carotid IMT correlated with conventional cardiovascular risk factors. Furthermore, high PWV was a stronger predictor of early carotid atherosclerosis rather than hypertension, dyslipidemia, and IFG in a Japanese general population.
Abstract 3764: Increased shedding of Endothelial Microparticles following Anti-VEGF therapy of Human Proliferative Diabetic Retinopathy
Authors: Benzerroug Mounir , Leroyer Aurélie , Picaud Serge , Gaudric Alain , Brasseur Gérard , Tedgui Alain , Massin Pascale , Boulanger Chantal
Published: July 2021

Background:
Development of retinal neovascularization in proliferative diabetic retinopathy (PDR) is correlated to vitreous VEGF levels. Intravitreal administration of Bevacizumab, a humanized recombinant antibody that binds all isoforms of VEGF, causes at least short-term involution of retinal neovascularization. We hypothesized that endothelial microparticles (MP), which are submicron membrane vesicles released following endothelial cell activation or apoptosis, accumulate in vitreous fluid from patients with PDR following anti-VEGF therapy.

Methods and results:
Undiluted vitreous fluid samples were collected at the start of standard surgery for the treatment of retinal disease in diabetic (D, n=14, 61±3yrs, 7.5±0.2% HbA1c) and non-diabetic (ND, with macular hole, epiretinal membrane or retinal detachment; n=15, 65±4yrs) patients. Four patients with PDR received intravitreal injection of Bevacizumab (50 μL; 25 μg/ μL) one week before surgery. Levels and cellular origins of MP in vitreous fluid were analysed by flow cytometry, using markers for platelet (CD41), endothelial (CD144), microglial (Bandeiraea Simplicifolia Lectin; ILB4) and photoreceptor (Arachis hypogaea Lectin; PNA) cells. Vitreous levels of endothelial and platelet MPs were markedly increased in PDR when compared to ND patients (139±53 vs 21±5 CD41+MP/μl (p=0.02); 238±61 vs. 62±12 CD144+MP/μl (p=0.004); respectively). Levels of MPs of microglial or photoreceptor origin did not differ significantly in D and ND vitreous samples (89±51 vs. 17±6 PNA+MP/μl (p=0.234); 47±25 vs. 20±13 ILB4+MP/μl (p=0.32); respectively). Intravitreal injection of anti-VEGF antibody led to a tenfold increase in endothelial MPs shedding (2418±673 CD144+MP/μl) and a complete disappearance of platelet-derived CD41+MPs in PDR vitreous samples. Anti-VEGF treatment also reduced microglial ILB4+MPs levels (3±3 MP/μl; p<0.16).

Conclusion:
Microparticle identification in vitreous samples indicates that local anti-VEGF therapy induces massive vascular endothelial cell apoptosis. In addition, augmented platelet MPs levels in diabetic vitreous samples suggests that PDR is associated with an increased endothelial permeability, which is restored to basal level by anti-VEGF therapy
Abstract 497: Normalization of Intracellular Calcium Signaling by Chronic Cardiac Resynchronization Involves Redox Modulation of Ryanodine Receptors.
Authors: Gyorke Inna , Terentyeva Radmila , Viatchenko-Karpinski Serge , Terentyev Dmitry , Nishijima Yoshinori , Feldman David S , Carnes Cynthia A , Gyorke Sandor
Published: July 2021

Cardiac resynchronization therapy (CRT) represents a promising treatment modality to alleviate LV dysfunction in humans with heart failure (HF). Using a canine chronic model of HF, we recently showed that CRT improves abnormal Ca2+ handling by reducing the diastolic Ca2+ leak from the SR through cardiac ryanodine receptors (RyR2s). Using the same models of HF and CRT therapy, we now demonstrate that the specific molecular mechanism for improved RyR2-mediated Ca2+ signaling involves partial restoration of RyR2s from post-translational oxidative modifications. RyR2 expression was markedly reduced in HF and restored to control levels after CRT. Single RyR2 channel activity from HF and CRT groups were recorded using the lipid bilayer technique. In both HF and CRT groups two functional types of RyR2s could be clearly distinguished based on their overall activity as well as sensitivities to luminal (
trans
) Ca2+ and cytosolic (
cis
) Mg2+: high-Po (open probability) and low-Po RyR2s; in contrast to normal controls (only low-Po). High-Po RyR2s in both groups exhibited enhanced sensitivity to
trans
Ca2+ and increased resistance to inhibition with
cis
Mg2+. These properties of the high Po RyR2s define the hyperactive, i.e. leaky RyR2 behavior in HF. Low-Po RyR2s had functional properties which did not differ from those observed in RyR2s from normal hearts. In HF ~80% of the RyR2s were high Po, while only ~20% were low Po RyR2s. Following CRT, the fraction of low Po RyR2s increased (to ~60%) while the remainder had high-Po behavior. High-Po channels could be partially normalized by the reducing agent DTT; whereas low-Po channels could be converted to the high Po type by treatment with the oxidative agent DTDP. These results suggest that RyR2 alterations in HF and normalization by CRT occur by redox modulation of a small number of critical sites susceptible to reversible oxidative modification. Additionally, the altered balance of the RyR2 functional fractions following CRT could reflect replacement of irreversibly modified RyR2s by newly synthesized protein, under condition of reduced oxidative stress. These data suggest that altered redox modulation contributes to abnormal function of the RyR2s in HF and that improved RyR2 redox balance may contribute to the efficacy of CRT.
Abstract 500: High Basal Ca
2+
/ Calmodulin Kinase II Activity Modulates Spontaneous Sarcoplasmic Reticulum Ca
2+
Cycling That Drives Normal Automaticity in Sinoatrial Nodal Cells
Authors: Li Yue , Sirenko Syevda G. , Vinogradova Tatiana M. , Lyashkov Alexey E. , Zhu Weizhong , Juhaszova Magdalena , Ziman Bruce , Wang Su , Lakatta Edward G.
Published: July 2021

The crucial dependence of normal automaticity of sinoatrial nodal cells (SANC) on CaMKII signaling has previously been linked to an effect to facilitate recovery from inactivation of L-type Ca
2+
channels. More recently, however, it has been discovered that spontaneous, rhythmic, local Ca
2+
releases (LCR’s) from sarcoplasmic reticulum (SR) activate Na
+
/Ca
2+
exchanger current, imparting an exponential increase to the later part of the spontaneous depolarization that brings the surface membrane to threshold to fire an action potential (AP). Here, in single isolated intact SANC, using the phosphorylation site-specific polyclonal antibody, we show (Fig. A

) that, basal state phospholamban (PLB) phosphorylation at Thr-17, a CaMKII phosphorylation site, is over 3 times greater in SANC than in ventricular cells (VC). The CaMKII inhibitor, KN-93, but not its inactive analog, KN-92, markedly inhibits (by 80%) PLB Thr-17 phosphorylation (Fig. B

). Confocal imaging of saponin permeablized SANC, superfused in physiological solution with 150nM free Ca
2+
and 0.5mM EGTA, showed that KN-93 reduced the LCR frequency by 80% (from 5.6 ± 1.5 to 1.1 ± 0.3/1s × 100 μm) and size by 50% (from 4.0 ± 0.3 to 2.0 ± 0.3 μm). Thus, in addition to an effect on L-type Ca
2+
channels, the high basal CaMKII activation (indexed by PLB phosphorylation at Thr-17) has a major effect to determine the characteristics of spontaneous LCR’s that initiate AP’s and control normal automaticity of SANC.
Abstract 3789:
Nessun Dorma
: Have the Risks of Rosiglitazone been Exaggerated?
Authors: Diamond George A , Kaul Sanjay
Published: July 2021

Background
A highly publicized meta-analysis of 42 clinical trials comprising 27,844 diabetics ignited a firestorm of controversy by charging that treatment with rosiglitazone was associated with a “…worrisome…” 43% greater risk of myocardial infarction (
p
=0.03) and a 64% greater risk of cardiovascular death (
p
=0.06).

Objective
The investigators excluded 4 trials from the infarction analysis and 19 trials from the mortality analysis in which no events were observed. We sought to determine if these exclusions biased the results.

Methods
We compared the index study to a Bayesian meta-analysis of the entire 42 trials (using odds ratio as the measure of effect size) and to fixed-effects and random-effects analyses with and without a continuity correction that adjusts for values of zero.

Results
The odds ratios and confidence intervals for the analyses are summarized in the

Table

.

Odds ratios for infarction ranged from 1.43 to 1.22 and for death from 1.64 to 1.13. Corrected models resulted in substantially smaller odds ratios and narrower confidence intervals than did uncorrected models. Although corrected risks remain elevated, none are statistically significant (*p<0.05).

Conclusions
Given the fragility of the effect sizes and confidence intervals, the charge that roziglitazone increases the risk of adverse events is not supported by these additional analyses. The exaggerated values observed in the index study are likely the result of excluding the zero-event trials from analysis. Continuity adjustments mitigate this error and provide more consistent and reliable assessments of true effect size. Transparent sensitivity analyses should therefore be performed over a realistic range of the operative assumptions to verify the stability of such assessments especially when outcome events are rare. Given the relatively wide confidence intervals, additional data will be required to adjudicate these inconclusive results.
Abstract 511: Mitochondrial Complex I -Regulated Alteration of Carbohydrate Oxidation and Energy Metabolites Reduces Ischemia-reperfusion Injury in Hearts from Mice Exposed to Moderate Ethanol Intake
Authors: Zhou Hui-zhong , Ma Xiaokui , Cecchini Gary , Simonis Ursula , Gray Mary O
Published: July 2021

Background:
Moderate alcohol consumption is cardioprotective in large part through mechanisms that converge on mitochondria. As a primary entry point for reducing equivalents into the respiratory chain, the state of complex I activation has important consequences for overall mitochondrial function and cell homeostasis.

Hypothesis
: Complex I is a key control point in regulation of carbohydrate oxidation and energy production that influence the extent of cardiac injury in hearts from ethanol-fed animals subjected to ischemia-reperfusion (I/R).

Methods and Results:
Isolated hearts from C57BL/6 mice fed 10% ethanol (vol/vol) as drinking water for 16 weeks (E) and age-matched controls were subjected to 30 min global ischemia and 30 min reperfusion. Hemodynamics showed E hearts had better contractile recovery (left ventricular developed pressure 62±6 vs. 24±5 mmHg) and less cell damage (creatine kinase release 0.32±0.1 vs. 0.65±0.1 U/min/g) than controls after reperfusion. Mitochondrial NADH-Oxidase (1.2±0.2 vs.0.58±0.1 μg/m/mg), NADH-ubiquinone reductase (complex I, 1.04±0.2 vs. 0.48±0.1 μg/m/mg), state 3 oxygen consumption rates (266±28 vs. 152 ± 18 ngAtomO/m/mg), respiratory control ratios (5.2±0.4 vs. 3.1±0.2), aconitase activity (0.73±0.2 vs. 0.48±0.1 μmol/m/mg), and lipid peroxidation (MDA 216±22 vs. 348±14 nmol/g ) were significantly improved in E hearts after I/R compared to control hearts (all P<0.05, n=3–12). EM showed that the severity of mitochondrial ultrastructure deformation in E hearts was attenuated. In addition, high resolution 1H NMR spectroscopy revealed that the myocardial metabolites alanine, glycine, creatine/phosphocreatine, NAD, total adenosine nucleotide, and ATP were better preserved, whereas lactate and succinate were reduced in E heart tissue extracts relative to control hearts.

Conclusions:

Moderate alcohol consumption reduces myocardial I/R injury.

The mechanism of the cardioprotection in part depends on mitochondria -mediated survival pathways.

Within the mitochondria, preservation of complex I activity is critical for maintaining overall respiratory function and cardiac energy generation.
Abstract 159: Protective Effect of Metallothionein in Ischemic Hindlimb against Oxidative Stress Induced by Benzo[
a
]pyrene
Authors: Ichihara Sahoko , Ichihara Gaku , Murohara Toyoaki , Yamada Yoshiji
Published: July 2021

Background:
A wide range of biological responses to and toxic effects of exogenous compounds, such as polycyclic and halogenated aromatic hydrocarbons and dioxins, is mediated by the aryl hydrocarbon receptor (AHR). Given that smoking is an important risk factor for ischemic heart disease and peripheral vascular disease, we hypothesized that benzo-[
a
]pyrene (B[a]P), a prototype carcinogen of tobacco smoke, might impair angiogenesis and AHR might play an important role in the regulation of angiogenesis after exposure to B[a]P. The present study investigated this hypothesis in a surgical model of ischemia.

Methods and Results:
Ischemia was produced by femoral artery ligature in the AHR gene-deficient (AHR
−/ −
) and wild type (WT) mice. B[a]P was administered by oral gavage in corn oil (10 ml/kg) at 125 mg/kg once per week beginning at 12 weeks of age (each group; n = 8). Laser Doppler perfusion analyses showed that the ischemic/nonischemic blood flow ratio of WT mice exposed to B[a]P was significantly reduced compared with that of control WT mice (0.67 ± 0.03 vs. 0.78 ± 0.02, P < 0.05) at 3 weeks after surgery. Furthermore, the blood flow ratio was significantly greater in AHR
−/ −
mice exposed to B[a]P than in WT mice exposed to B[a]P (P < 0.05). At 3 days after ligature, the abundance of cytochrome P450 1A1 mRNA, determined by quantitative RT-PCR analysis, was markedly greater in both ischemic and nonischemic hindlimbs of WT mice exposed to B[a]P than in those of AHR
−/ −
mice expose to B[a]P. The abundance of metallothionein I and II mRNA was significantly greater in the ischemic hindlimb than in the nonischemic hindlimb among all groups and was, moreover, significantly greater in the ischemic hindlimb of WT mice exposed to B[a]P than in that of AHR
−/ −
mice expose to B[a]P.

Conclusions:
The results show that the deletion of AHR gene reduced the adverse effects of exposure to B[a]P on angiogenesis. Our results also suggest that hypoxia in ischemia tissues activates the expression of metallothionein I and II, which may have protective effects against B[a]P-induced oxidative stress responses.
Abstract 39: Atropine for Patients with Out-Of-Hospital Cardiac Arrest
Authors: Nagao Ken , Sakamoto Tetsuya , Igarashi Masaki , Ishimatsu Shinichi , Sato Akira , Hori Shingo , Kanesaka Shigeru , Hamabe Yuichi , Kikushima Kimio
Published: July 2021

BACKGROUND AHA guidelines for cardiopulmonary resuscitation (CPR) have recommended that administration of atropine can be considered for asystole or pulseless electrical activity (PEA), because atropine has improved survival to hospital admission in a retrospective review (Ann Emerg Med, 1984), and is inexpensive, easy to administer, and has few side effects. However, there are insufficient data in humans.

METHODS We assessed the effects of atropine in 7,443 adults patients with asystole or PEA arrest from the SOS-KANTO study: a prospective, multicenter, observational trial. The medications for asystole or PEA arrest were managed according to the advanced cardiovascular life support algorithm of the CPR guidelines (i.e. a 1-mg dose of epinephrine was administered intravenously every 3 to 5 minutes and a1-mg dose of atropine was administered intravenously every 3 to 5 minutes; maximum total of 3 doses). The primary endpoint was a favorable neurological outcome 30 days after cardiac arrest.

RESULTS Of the 7,443 adult patients who had out-of-hospital cardiac arrest with asystole or PEA, I,708(23%) were treated with epinephrine and atropine and 5,735(77%) were treated with epinephrine. At baseline, the epinephrine and atropine group had significantly higher proportions of cardiac cause, witnessed arrest, and bystander CPR attempt than the epinephrine group. However, the two groups had a similar frequency of the favorable neurological outcome (0.3% in each group, p=0.805). Multiple logistic-regression analysis showed that the adjusted odds ratio for the favorable neurological outcome was 0.6 (95% CI 0.2–1.7, p=0.37) after epinephrine and atropine (compared with epinephrine). On the other hand, the epinephrine and atropine group had significantly higher rate of return of spontaneous circulation (ROSC) than the epinephrine group (35% vs. 23%, p<0.0001), and the adjusted odds ratio for ROSC was 1.6 (95% CI 1.4 –1.7, p<0.0001) after epinephrine and atropine (compared with epinephrine).

CONCLUSIONS We demonstrated that administration of atropine during management of asystole or PEA arrest did not increase the frequency of favorable neurological outcome, although the atropine favored initial ROSC.