tbuckley/cabot-search huggingface dataset:
Abstract 9707: Risk Reclassification of Mortality by Exercise Myocardial Perfusion Imaging
Authors: Angela Koh, Fei Gao, Felix Y Keng, Ru-san Tan, Terrance S Chua
Journal: Circulation (2012)

Background &amp; Aim: There is growing interest in net reclassification methods for evaluating incremental value of myocardial perfusion imaging (MPI) over clinical markers in clinical risk stratification. In exercise testing, net reclassification improvement (NRI) analysis has not been used in large patient cohorts. We aim to assess prognostic and net reclassification value of exercise and MPI by single-photon emission computed tomography to estimate mortality. Methods: We analyzed a prospective cohort of 11,156 patients referred for MPI between 2006 and 2008 (mean age 59 SD 12 years) with no known coronary disease. Mean follow-up time was 2.5 years with all-cause mortality as the primary outcome. In the first analysis involving 11,156 patients, the effect of MPI result on mortality was determined using Cox regression models. We then applied reclassification methodologies to compare between a clinical model that included age, gender, coronary risk factors, ability to exercise, versus a clinical + MPI model that included summed stress score (SSS) and ejection fraction. 6556 (59%) of patients underwent treadmill exercise testing using the Bruce protocol with computation of the Duke Treadmill Score (DTS). In a second analysis that involved only this subgroup of patients who exercised, we compared the clinical model comprising of age, gender, risk factors, SSS, ejection fraction, with a model that included DTS. All risk-estimates were categorized as &lt;1%, 1-3% and &gt;3% risk of mortality in 4 years. Results: Mortality occurred in 491 patients(4.4%). In clinical risk-adjusted models, the ability to exercise significantly estimated all-cause mortality (HR=0.147, 95% CI= 0.114 to 0.191, p&lt;0.001). Cox analysis showed that the addition of exercise improved incremental prognostic information (global chi-square increased from 639.58 to 758.02; p&lt;0.001) and risk prediction (NRI =0.06; 95% CI=0.05 to 0.07, p&lt;0.001). Amongst those who were able to exercise, the NRI by adding DTS was 0.08, 95%CI=0.04 to 0.12 (p&lt;0.001). Conclusion: In this large cohort of patients, the ability to exercise and Duke Treadmill Score added modest but significant incremental prognostic and risk prediction value over routine clinical and MPI variables in estimating all-cause mortality.
Abstract 9626: Tolerability of Apixaban-Insights From A Meta-Analysis of Discontinuation Rates in Randomized Trials
Authors: Ria Kundu, Saurav Chatterjee, Abhimanyu Ghose, Abhishek Sharma, Joydeep Ghosh
Journal: Circulation (2012)

Background: Apixaban is one of the most promising newer oral anti-coagulant agents being considered as a viable alternative for warfarin. However tolerability of the new drug, as reflected by rates of discontinuation in randomized trials for various indications, is conflicting. Objective: To evaluate the tolerability of apixaban by assessing discontinuation rates in trials of apixaban. Methods: A search was made of the PubMed, CENTRAL and EMBASE databases for randomized controlled trials that reported discontinuation rates of apixaban and comparator (could be pharmacologically active or not). The random effects (DerSimonian-Laird) Mantel-Haenszel (M-H) test was used to compare discontinuation rates of apixaban against comparators by evaluating relative risk (RR; 95% confidence interval [CI]). Statistical analysis was done with Review Manager V5.1 . Results: Analysis of eight RCTs (N=43277) revealed no significant increase in risk of discontinuation with apixaban compared to a variety of comparators (RR 1.09, 95% CI 0.91-1.30). On restricting the analysis to pharmacologically active agents, there was a definite trend towards improved discontinuation rates with apixaban, compared with warfarin, enoxaparin and aspirin (RR 0.95, 95% CI 0.90-1.00), without evidence of significant heterogeneity. Conclusion: Apixaban is well tolerated, when compared against a variety of comparators, as evidenced by comparable discontinuation rates in randomized trials. Figure: Forest Plot of Relative Risk of Discontinuation of Apixaban Compared with All and Pharmacologically Active Comparators in Randomized Trials
Abstract 9569: Incidence of Acute Coronary Syndrome in the General Medicare Population, 1992-2009: A Real-World Perspective
Authors: Gautam R Shroff, Brooke M Heubner, Jeff Schein, Concetta Crivera, Charles A Herzog
Journal: Circulation (2012)

Introduction: Acute coronary syndrome (ACS) is a major cause of mortality and morbidity among elderly patients in the US. We examined temporal trends in the incidence of ACS in Medicare patients over nearly two decades employing administrative data. Methods: The 5% Medicare database (~ 1.8 million pts/cohort yr) was used to identify ACS pts (age 65+, no ESRD) between 1992-2009. Medicare claims were used to identify patients hospitalized with ACS using the following ICD-9-CM diagnostic codes: acute myocardial infarction (AMI, 410) and unstable angina (UA, 411). Results: The incidence of ACS in the elderly Medicare population remained 2.4-2.5% between 1999-2002 and subsequently decreased to 1.7% by 2009 ("A" in the Figure). The trend was similar for all age, gender and race groups ("B" in the Figure) with the exception of patients &gt; 84 years, for whom the incidence of ACS increased from 2.8% in 1992 to 3.4% in 2002, before declining to 2.6% in 2009. The decrease in incidence of ACS since 2001 was driven by a decrease in diagnosis of UA (1.6-1.7% in 1992-1997 to 0.6% in 2009) but not in the diagnosis of AMI (holding steady between 1.2-1.4%), perhaps reflecting the introduction of more sensitive cardiac biomarkers. Conclusion: Improved cardiovascular outcomes in the US have also impacted elderly patients with ACS. In the last decade, there has been a steady progressive decline in the incidence of ACS in Medicare patients.
Abstract 9672: Older Age at Fontan is Associated with Improved Exercise Performance in the Current Era
Authors: Elijah H Bolin, Shiraz Maskatia, Amanda Tate, William Payne, Christopher J Petit
Journal: Circulation (2012)

Introduction: Exercise capacity is associated with mortality and morbidity in Fontan patients. Debate continues about modifiable factors impacting exercise. Hypothesis: We assessed the hypothesis that later Fontan completion and larger branch pulmonary arteries are associated with better exercise. Methods: We performed a retrospective review of exercise stress test (EST) data from 2003 to 2011 in Fontan patients undergoing the Bruce protocol. The primary marker of performance was percent of predicted maximum oxygen consumption (%MVO 2 ). Pulmonary artery caliber was assessed using tomographic or angiographic imaging, and included if imaging was performed four years before or after the EST. Imaging or catheterization data were excluded if surgical or catheterization based interventions were performed such that a patient's anatomy changed between the time of EST and imaging. Analysis was performed on the entire cohort and a Current Era group defined as patients who underwent Glenn ≤ 1 year, did not have a pacemaker at EST, and achieved a respiratory exchange ratio ≥1.0. Results: During the study period, 144 patients were identified (mean age 13.7 ± 5.3 years). Among Current Era patients (n = 55), both older age at Fontan (R = 0.286, p = 0.034) and Nakata index (R = 0.389, p = 0.049) were positively associated with %MVO 2 . There were negative associations between time from Fontan to EST (R = -0.367, p = 0.006) and Fontan pressure (R = -0.501, p = 0.015). For the entire cohort, longer time from Fontan to EST (R = -0.461, p &lt; 0.001) and higher Fontan pressure (R = -0.271, p = 0.046) were associated with diminished performance. In both groups, multivariable regression was performed for variables that were significantly correlated ( p &lt; 0.05) with %MVO 2 . Time from Fontan to EST was significant for Current Era patients (slope coefficient -3.2, p = 0.010) and the entire cohort (slope coefficient -1.6, p = 0.005). Conclusion: Older age at Fontan after Glenn and shorter time from Fontan to EST are associated with higher %MVO 2 , suggesting that Fontan completion should be delayed in the current era. Smaller Nakata index and elevated Fontan pressure negatively correlate with %MVO 2 , providing a rationale for intervening on stenotic pulmonary arteries.
Abstract 9595: A Novel Niacin Analog (ARI-3037MO) Induces Favorable Plasma Lipid Changes Without Flush in Single and Multiple Ascending Dose Placebo Controlled Trials in Normal Healthy Volunteers
Authors: Claude Benedict, Joel Neutel, William Bachovchin, Christopher Kiritsy
Journal: Circulation (2012)

INTRODUCTION: Despite niacin’s (NA) beneficial effects on lipids, it’s use is limited by side effects, such as flushing, itching, and increases in liver enzymes and blood glucose. These effects, particularly flushing, lead to poor compliance and persistence in clinical use. ARI-3037MO is an orally active, novel, NA analog that produces significant lipid altering effects at least as effective as NA on low density lipoproteins (LDL-C), triglycerides (TG) and high density lipoproteins (HDL-C) in preclinical studies without flushing. METHODS: To evaluate safety and pharmacokinetics of ARI-3037MO in humans, we conducted a single ascending dose (SAD) trial and a multiple ascending dose (MAD) trial in healthy volunteers. In SAD study, five doses of ARI-3037MO QD were evaluated in 30 subjects (n=6 per dose; 17 males, 13 females). Ten additional subjects received matching placebo. In MAD trial, four doses of ARI-3037MO [(0.5g (n=8), 1g (n=8), 2g (n=9) &amp; 3.5g (n=9)] QD were evaluated in 34 healthy volunteers (24 males, 10 females) for 14 or 28 days (2g QD cohort only). Eight additional subjects received matching placebo. RESULTS: In SAD trial all doses (0.5g - 6g/day) of ARI-3037MO, were well tolerated with no evidence of flushing, itching or other skin changes even at the 6g QD dose. No liver function or glucose abnormalities were observed. There was a reduction in TG (-56.7 +/- 37.0 mg/dl; mean+/- SEM; p &lt; 0.05 ANOVA) and an increase in HDL-C (+ 7.7 +/- 1.6 mg/dl; p &lt; 0.05 ANOVA) in the 6g cohort. In MAD trial, all doses were well tolerated with no evidence of flushing, itching or other skin changes even at the highest dose. No liver function or glucose abnormalities were observed. There was a significant reduction in TGs with 2g dose given for 28 days as well as a trend toward reduction in LDL-C. Following single or multiple dosing, ARI-3037MO was rapidly absorbed and plasma drug levels showed good dose proportionality. CONCLUSION: The absence of any adverse effects (including flush, increases in liver enzymes and blood glucose) at all doses in the SAD and MAD studies, combined with encouraging lipid effects in these short duration trials indicates that ARI-3037MO represents a potential transformational niacin-based therapy for patients with dyslipidemia and metabolic syndrome.
Abstract 9496: Multiphasic Triacylglycerol Dynamics in the Intact Heart During Acute In Vivo Overexpression of CD36
Authors: Andrew N Carley, Jian Bi, Xueron Wang, J. Michael O'Donnell, E Lewandowski
Journal: Circulation (2012)

The cardiac triacylglycerol (TAG) pool is a dynamic buffer for the intracellular availability of long chain fatty acid (LCFA), a critically important source of nuclear receptor ligand and oxidative fuel for the beating heart. In addition, the TAG pool prevents the accumulation of potentially toxic LCFA derivatives. However, specific kinetics of LCFA incorporation into TAG in the intact, beating heart are largely uncharacterized, and the mechanisms linking uptake and storage dynamics have until now remained elusive. This work examines TAG dynamics in the intact rat heart, under normal conditions and in response to acute, gene expression-induced changes in in vivo protein-mediated lipid uptake. Dynamic mode 13C NMR of beating rat hearts elucidated multiple kinetic processes in 13C-palmitate incorporation into TAG: an initial saturable exponential component and a slower linear rate. While previous work indicates the linear component to reflect TAG turnover, we hypothesized the saturable exponential to reflect transport of LCFA across the sarcolemma. Thus, we overexpressed the LCFA transporter, CD36 through cardiac-specific adenoviral infection (adv.CD36) in vivo. Within 72 hours, CD36 expression was increased 40% in intact hearts, accelerating the exponential phase (highlighted in Figure 1) with a 60% reduction in the time constant relative to PBS infused hearts (adv.CD36: 1.29±0.24, PBS: 3.18±0.53 min, n=5, p&lt;0.05). CD36 overexpression also increased TAG turnover rates and the corresponding expression of key a TAG synthase, DGAT1, and lipase, ATGL. The results demonstrate coupling LCFA uptake across the sarcolemma to intracellular TAG dynamics and coordination of these events by reciprocal control of gene expression in the heart. Thus, a model system of reciprocal regulation between altered LCFA uptake, and TAG synthesis / lipolysis is elucidated that buffers potentially reactive free fatty acids while maintaining ligands and high energy fuel capacity.
Abstract 96: Healthcare Disparity: Post--Cardiac Arrest Care Knows No Color Barriers
Authors: Shaker M Eid, Aiham Albaeni, Dhananjay Vaidya, Nisha Chandra-Strobos
Journal: Circulation (2012)

Background: A clinical manifestation of several diseases (e.g. Diabetes Mellitus, Hypertension, and Coronary Artery Disease) in African-Americans and other non-Caucasian populations is cardiac arrest. Since many studies have confirmed healthcare disparities in patients of color, we explored whether cardiac arrest care varied by race in a large metropolitan hospital drawing from a diverse population of over half a million (38% non-Caucasian 35% African-American) served by a diverse physician group. Methods: We evaluated 170 survivors of non-traumatic out-of-hospital cardiac arrest (age 63 ± 16, 62.4% males). To index appropriateness and vigor of resuscitation and post-arrest care, we studied the factors listed in the table below together with: hypothermia therapy, withdrawal of care and survival to discharge in Caucasians vs. Non-Caucasians. Data were analyzed using Chi-square test and T-test. Data are reported as percentage, mean and standard deviation or median and 25 th /75 th quartiles. Results: Of 170 patients, 47 were non-Caucasian with 44 being African-American and 3 Hispanic. The incidence of VF/VT was comparable in Caucasians and non Caucasians as was the time to Return of Spontaneous Circulation (ROSC), the use of epinephrine, or therapeutic hypothermia. Similarly, care delivery was comparable with no difference in the length of hospital stay, use of testing, withdrawal of support or early care withdrawal. There was a trend to a greater likelihood of bystander CPR in non Caucasians; however, survival to discharge or neurological status was not affected, and remained comparable in both patient groups. Conclusion: These data demonstrate that irrespective of healthcare disparities that may exist early during disease, following cardiac arrest, therapy is color blind.
Abstract 9664: Utilization Patterns of Anticoagulants in Non-Valvular Atrial Fibrillation after the entry of Novel Oral Anticoagulants in the United States
Authors: Melissa Hamilton, Hugh Kawabata, Xianchen Liu, Diana Brixner, Joseph Biskupiak
Journal: Circulation (2012)

Introduction: Anticoagulants including warfarin and novel oral anticoagulants (NOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. Limited data are available on real-world use of warfarin and NOACs in these patients since the entry of NOACs into the US market in October, 2010. Hypothesis: Warfarin and NOACs are prescribed for stroke prevention differentially based on patient characteristics. Methods: Incident cases of NVAF were identified from GE electronic medical records database between 11/2010 and 08/2011 based on ICD-9 codes 427.31 and 427.32. Baseline characteristics were obtained from medical record history prior to diagnosis. Patients were assessed over 6 months for initiation of warfarin or NOAC (dabigatran or rivaroxaban). Factors associated with anticoagulant initiation and NOAC initiation were examined using multivariate logistic regression analyses. Results: Among 19,730 NVAF patients, mean age was 70.8 years, 45.5% were female, and 36.5% initiated an anticoagulant (31.0% warfarin and 5.5% NOAC). CHADS2 score differed across treatment groups with CHADS2 ≥2 found in 47.9%, 45.6% and 36.3% of patients receiving warfarin, NOACs, and no anticoagulants, respectively (p &lt; 0.001). Age, prescriber type, hypertension, diabetes, CHF, prior stroke/TIA, prior MI, and history of GI or other bleeding were significantly associated with the use of anticoagulants. NOAC use was more likely than warfarin in patients with hypertension (OR=1.19), history of GI bleeding (OR=1.40) and prior aspirin use (OR=1.81) but less likely in those with history of CHF (OR=0.70). Conclusions: Since the entry of NOACs, over 60% of newly diagnosed NVAF patients did not receive anticoagulants despite 36% of those patients having CHADS2 score ≥2. GI bleeding history, CHF, and prior aspirin use were major clinical factors associated with NOAC use. Further research is warranted to examine changes in anticoagulant treatment over time.
Abstract 9688: Association of Common Variations on Chromosome 4q25 and Left Atrial Volume in Patients with Atrial Fibrillation
Authors: Hirad Yarmohammadi, Hana Hoyt, Irfan M Khurram, Rozann Hansford, Menekhem Zviman, Stefan L Zimmerman, Steven J Steinberg, Daniel P Judge, Gordon F Tomaselli, Henry R Halperin, Alan Cheng, David D Spragg, Charles A Henrikson, Sunil Sinha, Joseph E Marine, Ronald Berger, Hugh Calkins, Saman Nazarian
Journal: Circulation (2012)

Objectives: To examine the association between single nucleotide polymorphisms (SNPs) near PITX2 and left atrial size in patients with atrial fibrillation (AF). Background: Recent studies have shown that several genetic variants near the PITX2 locus on chromosome 4q25 are associated with AF. However, the mechanism that mediates this association remains unclear. Basic murine studies suggest that reduced PITX2 expression is associated with left atrial dilatation. Methods: We prospectively enrolled 96 patients (mean age 60 ± 10 yrs, 72 % male) with drug resistant AF (57% paroxysmal, 38% persistent and 5% longstanding persistent) who underwent catheter ablation. Following DNA extraction from blood obtained pre-operatively, SNPs rs10033464 and rs2200733 were genotyped using the Sequenom MassARRAY. Left atrial volume (LAV) was determined using 3-dimensional imaging (CT or MRI prior to first ablation) by investigators blinded to genotype results. Results: The minor allele frequency at SNPs rs10033464 and rs2200733 were 0.14 and 0.25, respectively. Using multivariate linear regression, the minor allele at rs10033464 (co-dominant model) was independently associated with larger LAV (P = 0.037) after adjustment for age, gender, BMI, type of AF, left ventricular ejection fraction, and history of hypertension. However, no association was found between rs2200733 variant alleles and LAV (P = 0.82). Conclusion: SNP rs10033464 near the PITX2 locus on 4q25 is significantly associated with LAV. Left atrial dilatation may mediate the association of common variants at 4q25 with AF.
Abstract 9345: CaMKII Integrates Oxidative Stress and Calcium Signaling in Atrial Fibrillation
Authors: Anil Purohit, Paari Dominic Swaminathan, Adam Rokita, Biyi Chen, Niels Voigt, Olha M Koval, Elizabeth D Luczak, Zhan Gao, Xiaoqun Guan, Na Li, Ramzi N El-Accaoui, Baoli Yang, Robert M Weiss, Xander H Wehrens, Long-Sheng Song, Dobromir Dobrev, Mark E Anderson
Journal: Circulation (2012)

Introduction: Emerging evidence suggests that abnormal calcium (Ca 2+ ) signaling and oxidative stress play an important role in Atrial Fibrillation (AF). We hypothesized that oxidative activation of CaMKII leads to increased sarcoplasmic reticulum (SR) Ca 2+ release and delayed afterdepolarizations (DAD) to cause AF. Methods: We established a mouse model of AF by implanting subcutaneous angiotensin II (Ang II) eluting osmotic pumps for three weeks followed by in vivo right atrial burst pacing. We measured oxidized CaMKII (ox-CaMKII) in atria from Ang II infused mice and from patients in AF or sinus rhythm. We developed ox-CaMKII resistant knock-in mice by replacing key methionines (281/282) with valines (MM-VV) in the predominant myocardial isoform (CaMKIIδ) and mice with transgenic myocardial expression of methionine sulfoxide reductase A (MsrA), an enzyme that reduces ox-CaMKII, to test if ox-CaMKII was required for AF promoted by Ang II. Results: ox-CaMKII is elevated in atrial tissue from patients with AF and from mice infused with Ang II compared to patients in sinus rhythm or mice infused with saline. Mice treated with Ang II are highly susceptible to AF, while AF was rarely induced in saline infused mice. MM-VV mice and MsrA transgenic mice were resistant to AF and did not show increased ox-CaMKII after Ang II infusion. Atrial myocytes from Ang II treated wild type mice showed significantly increased DADs and SR Ca 2+ sparks compared to saline treated controls. Ang II treatment did not increase calcium sparks in MM-VV mice. Conclusions: Oxidative activation of CaMKII is an important molecular pathway for AF and strategies that decrease the level of ox-CaMKII can prevent AF.
Abstract 9955: Cooperative Operation of PGD <sub>2</sub> /FP and 15d-PGJ <sub>2</sub> /nrf2 Pathway in the L-PGDS-Mediated Cardioprotection
Authors: Yoshinori Katsumata, Motoaki Sano, Ken Shinmura, Tomohiro Matsuhashi, Shugo Tohyama, Jin Endo, Atsushi Anzai, Cardex Yan, Keiishi Fukuda
Journal: Circulation (2011)

Background Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed in adult cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD2-dominated activation of prostanoid biosynthesis via induction of phospholipase A2 and cyclooxygenase-2, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD2-dominated activation of prostanoid biosynthesis. Methods and Results (1) In cultured neonatal rat cardiomyocytes, PGD2 strongly activated ERK in a dose-dependent manner, although canonical PGD2 receptors, including DP (PGD2 receptor) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors, were hardly expressed on cardiomyocytes. (2) Interestingly, PGD2 bound to FP receptor (the canonical PGF2α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor was abundantly expressed in cardiomyocytes. (3) PGD2-induced ERK activation was completely blocked by FP antagonist or siRNA-mediated knockdown of the FP, but not by DP and CRTH2 antagonist and siRNA-mediated knockdown of DP and CRTH2. (4) PGD2 activated ERK in Langendorff perfused DP-knock-out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while it did not activate ERK in FP-KO hearts. (5) Dexamethasone protected hearts against ischemia-reperfusion injury in L-PGDS-dependent manner. The dexamethasone-mediated cardioprotection was partially cancelled in FP-KO mice. (6) Gene-chip and Q-PCR analysis revealed that dexamethasone induced Nrf2-dependent antioxidant gene expression in wild-type mice, but not in L-PGDS KO mice. Dexamethasone-mediated cardioprotection against ischemia-reperfusion injury was partially attenuated in Nrf-2 KO mice. (7) In cultured cardiomyocytes, PGD2 had little effect on Nrf2 activation, while 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which is formed from PGD2, strongly activated Nrf2. Conclusion PGD2 and 15d-PGJ2 are cooperatively involved in the L-PGDS-mediated cardioprotection against ischemia-reperfusion injury via FP receptor and Nrf-2 activation, respectively.