tbuckley/cabot-search huggingface dataset:
Abstract 11362: The Riser Pattern, a Novel Marker of Adverse Prognosis in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Takahiro Komori, Kazuo Eguchi, Toshinobu Saito, Satoshi Hoshide, Kazuomi Kario
Journal: Circulation (2016)

Introduction: The cardiovascular prognosis of heart failure with preserved ejection fraction (HFpEF) has been shown to be similar to that of heart failure with reduced ejection fraction (HFrEF). It is unknown which factors predict cardiovascular outcomes in HFpEF. Hypothesis: The abnormal pattern of circadian BP rhythm known as riser BP pattern is associated with adverse outcomes in HFpEF. Methods: We enrolled 516 hospitalized HF patients who underwent ambulatory BP monitoring (ABPM) (age, 69±13 yrs; 61% males [n=314] and 39% females [n=200]), and were followed up for 23±16 months. The combined endpoints consisted of all-cause mortality and cardiovascular events. Results: Combined endpoints were observed in 220 cases. In a Kaplan-Meier analysis, the riser BP pattern subgroup had a significantly higher incidence of combined endpoints than the other subgroups of the HFpEF patients (Figure). In a Cox regression analysis adjusted for significant variables, the riser BP pattern was a significant predictor of adverse outcomes in the HFpEF group (HR 3.01, 95%CI 1.54-6.08, p&lt;0.01), but not in the HFrEF group. Conclusions: The riser BP pattern was found to be a novel predictor of cardiovascular outcomes in patients with HFpEF.
Abstract 11235: Improvement of Defective Channel Function on RyR2 Mediated by CaMKII Activation Suppresses Arrhythmogenesis in TnT-related Hypertrophic Cardiomyopathy
Authors: Shinichi Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Yoko Okamoto, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
Journal: Circulation (2016)

Backgrounds: In Familial Hypertrophic Cardiomyopathy (FHC) caused by cardiac troponin T (cTnT) mutations, Ca 2+ sensitivity in myofilaments is increased, results in leading to sudden cardiac death. The activation of calcium/calmodulin-dependent protein kinase II (CaMKII) is known to be one of the key elements for the alteration of calcium handling in heart failure, presumably mediated through defective channel function of cardiac ryanodine receptor (RyR2). However, how cTnT mutations lead to lethal arrhythmias and abnormal calcium handling through defective RyR2 remains elusive. Here, we investigated the pathogenic role of CaMKII on aberrant Ca 2+ release through RyR2 for arrhythmogenesis in FHC hearts and therapeutic effects of dantrolene, which was found to correct inter-domain interactions between N-terminal and central domain of RyR2 in FHC-related cTnT-mutated transgenic mouse (TG; cTnT-delta160E). TG have been reported myocardial disarray in histology and increased Ca 2+ sensitivity in myofilaments. Methods and results: On confocal Ca 2+ imaging by fluo4-AM exposed to isoproterenol (ISO; 10 nmol/L), the Ca 2+ spark frequency (SpF:s-1·100μm-1) was much higher in TG cardiomyocytes (ISO-TG: n=11: 7.8±0.6; p&lt;0.05) than in non-TG (n=8: 3.4±0.4). It was largely reversed by CaMKII inhibitor {KN-93(1μM), n=7: 5.2±0.5; p&lt;0.05}, but not by PKA inhibitor (PKI){H-89(1μM), n=7: 7.3±0.4}. The significant increase of spontaneous Ca 2+ transient (sCaT), which was measured after sequential pacing at 5 Hz was appeared in ISO-TG (42.1%; p&lt;0.05 vs ISO-treated non-TG 14.0%), whereas it was again attenuated by CaMKII inhibitor (15.8%), but not by PKI (33.0%). These abnormal events in ISO-TG were reproduced by adding EGTA-AM into ISO-treated non-TG, suggesting that increased Ca 2+ buffering capacity, causing an increase in diastolic [Ca 2+ ], predisposes to aberrant Ca 2+ release events. Moreover, after the treatment of dantrolene (1μM), ISO-induced SpF (n=6: 5.2±0.3; p&lt;0.05 vs ISO-TG) and sCaT (25.9%) were decreased in TG. Conclusions: CaMKII activation may play a role in the development of abnormal calcium handling in FHC-linked cTnT mutated hearts, possibly through defective inter-domain interaction between N-terminal and central domain of RyR2.
Abstract 10824: A Novel Role of Endothelial Autophagy in the Regulation of Thrombosis <i>in vivo</i>
Authors: Jonathan W Yau, Yan Hou, Xi Lei, Azza Ramadan, Hwee Teoh, Adrian Quan, Krishna K Singh, Mohammed Al-Omran, Heyu Ni, Subodh Verma
Journal: Circulation (2015)

Background: Arterial thrombosis of native and graft vessels is the inciting event for acute coronary syndromes, and the cause of significant cardiovascular morbidity and mortality. Endothelial cell (EC) dysfunction is believed to play a central role in the pathobiology of thrombosis. ECs are activated upon atherosclerotic plaque rupture and induce the expression of tissue factor (TF) with resultant atherothrombotic sequelae. The molecular basis of how endothelial TF is unregulated remains unknown. We hypothesize that endothelial autophagy, a process involved in cellular homeostasis and stress responses, plays a causal role in the expression of TF, and via this mechanism modulates thrombosis. Methods: We generated EC-specific ATG7 knockout (EC-ATG7 -/- ) mice using CreLoxP technology. We used small interfering RNA (siRNA) to knockdown and characterize the effect of ATG7 inhibition in HUVECs. We also employed intravital microscopy in FeCl 3 -induced carotid and laser-induced cremaster artery injury to evaluate thrombosis. Results: siRNA-mediated knockdown of ATG7 in HUVEC resulted in decreased TF mRNA and protein expression by over 60% (N=3-5; p&lt;0.05). Mean TF mRNA level in EC-ATG7 -/- mice was 43% lower (p&lt;0.05) compared with WT mice, after FeCl 3 -induced carotid artery injury. Time to carotid artery occlusion was significantly prolonged in EC-ATG7 -/- mice compared with WT mice (15.5±2.0 and 31.0±4.0 min, respectively; N=10/group; p=0.003). The time to maximum platelet fluorescence intensity in EC-ATG7 -/- mice was significantly prolonged relative to that for WT mice (1.0±0.6 and 2.3±1.2 min, respectively; N=33-38 thrombi; p&lt;0.0001). Thrombi size, as determined by platelet fluorescence intensity, were significantly smaller in EC-ATG7 -/- vs. WT mice, (1.8±0.7 and 8.2±2.9, respectively; x10 9 ; p=0.049). Conclusions: Knockdown of ATG7 resulted in reduced TF expression in vitro and in vivo. Compared to WT mice, EC-ATG7 -/- mice exhibited 2-fold greater occlusion times and reduced thrombi formation across all models of thrombosis. Taken together, these findings are evidence that endothelial autophagy regulates thrombosis in a TF-dependent manner, and underscores a novel and previously unrecognized target for antithrombotic drug development.
Abstract 18079: B-Type Natriuretic Peptide is a Screening Tool to Rule Out Subclinical Left Ventricular Geometry and Diastolic Dysfunction in a Community-Based Population
Authors: Takuya Hasegawa, Masanori Asakura, Hideaki Kanzaki, Jiyoong Kim, Hiroshi Asanuma, Akira Funada, Yasuo Sugano, Takahiro Ohara, Toshihisa Anzai, Masafumi Kitakaze
Journal: Circulation (2013)

Background: LV hypertrophy and LV diastolic dysfunction are common and associated with the incidence of cardiac events in the general population. LV systolic and/or diastolic dysfunction and LV hypertrophy are associated with high B-type natriuretic peptide (BNP) levels. Plasma BNP levels have been reported to be a useful biomarker to detect various heart diseases in the general population. However, it has not been investigated whether plasma BNP levels are useful to detect LV hypertrophy and/or diastolic dysfunction in the general population. Methods: We studied 1162 community-dwelling subjects without obvious heart diseases (mean age, 63 +/- 11 years; 448 men, 714 women) who participated in annual health checkup in a rural Japanese community, Arita-cho. The population was divided into 5 groups referring to plasma BNP levels. LV diastolic dysfunction was determined with the waves of transmitral flow and mitral annular velocity. LV hypertrophy was defined as the top quintile of LV mass index. Results: The prevalence of LV hypertrophy and/or diastolic dysfunction increased along with increases in BNP levels(Table). The area under the receiver operating characteristic curve showed the modest ability of plasma BNP levels for detecting those subjects (0.640 95%CI 0.590-0.690 p&lt;0.001). An optimal threshold for the identification of the subjects with both LV hypertrophy and diastolic dysfunction was a BNP of 22.0 pg/ml with the sensitivity of 61%, the specificity of 58%, positive predictive value of 17%, and negative predictive value of 92%. Conclusion: BNP levels seem the useful screening tool to rule out, rather than detect, subclinical LV impairment in the community-based population.
Abstract 18024: The Efficacy and Safety of Rivaroxaban vs Warfarin in Patients Undergoing Atrial Fibrillation Ablation: A Meta-Analysis
Authors: Sandeep R Gangireddy, Anna P Koh, Katy E Bockstall, Stephen Keane, Alexander M Fisher, Jacob Koruth, Marc A Miller, Srinivas Dukkipati, Vivek Y Reddy
Journal: Circulation (2013)

Introduction: Rivaroxaban, an oral direct factor Xa inhibitor, is an alternative to warfarin for stroke prophylaxis in patients with atrial fibrillation (AF). Patients are increasingly undergoing AF ablation while taking rivaroxaban, but little is known regarding the safety of this approach. Methods: We performed a meta-analysis of studies which compared the use of peri-procedural rivaroxaban with warfarin in patients undergoing AF ablation. We identified 1 published randomized controlled trial and 5 abstracts; 3 observational studies with control groups, and 2 observational studies without control groups. Embolic complications were defined as stroke/TIA or pulmonary embolism, and bleeding complications as all major events requiring transfusion and minor events including pericardial effusion, femoral hematoma, and GI bleeding. Studies were stratified according to controlled vs. uncontrolled study design, and analyzed using the Mantel-Haenszel fixed effect model. Results: There were a total of 634 patients on rivaroxaban, and 479 patients on warfarin undergoing AF ablation. Mean age was 63, and CHADS2 score ranged from 0.9-3. Rivaroxaban was held 12-48 hours pre-procedure, resumed 6-24 hours post-procedure, and in 224 (35%) was uninterrupted. The composite embolic rate was 1.7% in the rivaroxaban group, and 1.5% in the warfarin group (p=NS). The composite bleeding rate was 11.5% the rivaroxaban group, and 10.5% in the warfarin group (p=NS). Meta-analysis using controlled studies (410 rivaroxaban vs. 479 warfarin patients) showed no difference in embolic complications (OR, 0.791; 95% CI, 0.246-2.541) and bleeding complications (OR, 1.214; 95% CI, 0.790-1.867) between the two groups (Figure). Conclusion: Rivaroxaban may be a safe alternative to warfarin anticoagulation in patients undergoing AF ablation. Further randomized controlled trials are needed to determine its relative safety and efficacy compared to warfarin peri-ablation.
Abstract 18019: Race and Sex Sensitive Stroke Risk Prediction: Analysis of Pooled Data From Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) Cohorts
Authors: Dilip K Pandey, Weihan Zhao, Dulal K Bhaumik, Philip B Gorelick
Journal: Circulation (2013)

Context: A risk assessment tool predicting increased risk of first stroke helps to identify at-risk individuals and aid in development of intervention strategies leading to the primary prevention of stroke. Most relied-upon Framingham Heart Study (FHS) stroke risk profile (FRS) does not include race due to lack of information on race other than white in FHS. Objective: To develop a race and sex sensitive risk score for incident stroke. Methods: Risk prediction functions were estimated using pooled data from the ARIC and CHS studies on 16,379 participants (55% women, 23% black) with 1,363 (8.3%) incident stroke during 263,295 person-years with median follow-up 18.3 years. Study sample included individual ages 45-84 years and free of stroke and cancer at the initial examination. Study sample did not include stroke events or individuals lost due to other events or follow-up during the first year as well as individuals with missing data on factors of interest. Cox proportional hazards regression analysis was performed after confirming the proportionality of hazards. Akaike (AIC) and Bayesian information criterion (BIC) was used to develop the best fitting model. Results: The risk equation included age, sex, race (non-black/black), left ventricular hypertrophy, peripheral arterial disease, current smoking, prior myocardial infarction, atrial fibrillation (AF), waist to hip ratio, systolic blood pressure (SBP), and diastolic blood pressure, use of antihypertensive therapy (HTNMED), fasting blood sugar and serum creatinine. The risk equation also included interactions between age x race, age x sex, race x AF, and SBP x HTNMED. All predictors included were significantly associated at p &lt;0.05 except for race x AF (p = 0.078). The risk equation demonstrated good discrimination (Harrell’s C = 0.7877) with receiver operator (ROC) curve statistics for 10-year stroke risk of 0.7521 for non-black and 0.7012 for black. The ROC curve statistics for 10-year stroke risk estimated from the FRS were 0.7099 for non-black and 0.6552 for black. Conclusion: This improved stroke risk predictions derived from a large population based data provide race and sex sensitive risk prediction of first stroke based on predictors readily available during routine clinical examination.
Abstract 10208: Differences in Natriuretic Peptide Levels by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis
Authors: Deepak K Gupta, Lori B Daniels, Susan Cheng, Christoper DeFilippi, Michael H Criqui, Alan Maisel, Joao A Lima, Hossein Bahrami, Phillip Greenland, Mary Cushman, Russell Tracy, David Siscovick, Alain Bertoni, J. Jeffrey Carr, Thomas J Wang
Journal: Circulation (2015)

Introduction: Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardio-metabolic actions including natriuresis, diuresis, and vasodilation. Low NP levels have been associated with increased risks of hypertension and diabetes, conditions with variable prevalence by race/ethnicity. Heritable factors underlie a significant proportion of the inter-individual variation in NP levels, but the specific influence of ancestry is unknown. Methods: In 4,162 individuals (40% White, 24% Black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline (2000-2002) in the Multi-Ethnic Study of Atherosclerosis, multivariable adjusted linear regression and restricted cubic splines were used to examine differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to self-reported race/ethnicity or ancestry determined from genetic ancestry informative markers. Results: NT-proBNP levels were significantly lower in Black and Chinese individuals than in White individuals, and were intermediate in Hispanics (Figure 1). Self-identified Blacks and Hispanics were the most genetically admixed groups. Among individuals self-identified as Black, a 1 standard deviation (14%) increase in genetic European ancestry was associated with 8% higher (95%CI, 1 to 16%) NT-proBNP. Among Hispanic individuals, genetic European ancestry was also positively associated with NT-proBNP levels, while African ancestry was negatively associated with NT-proBNP (Figure 2). Conclusions: NP levels differ substantially according to race/ethnicity, with the lowest levels among Black and Chinese individuals. Racial/ethnic differences in NP levels appear to have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP levels, respectively. Relatively low NP levels may, in part, contribute to racial/ethnic disparities in cardio-metabolic disease susceptibility.
Abstract 17984: Protective Role of Dicer in Macrophages During Atherogenesis
Authors: Yuanyuan Wei, Kathrin Heyll, Christian Weber, Andreas Schober
Journal: Circulation (2013)

Atherosclerotic lesion development is characterized by the subendothelial accumulation of lipid-laden macrophages. It is known that microRNAs (miRs) are generated by the RNase Dicer and play important roles in macrophage function by negatively regulating post-transcriptional gene expression. Previously, we found that macrophage-derived miR-342-5p enhances atherosclerosis by fostering inflammatory macrophage activation. However, the impact of Dicer-dependent miR expression in macrophages during atherosclerosis is unclear. To study the role of Dicer in macrophages in atherosclerosis, we fed Apoe-/- mice with a myeloid cell-specific deletion of Dicer (LysMCre-Dicerflox) and littermate controls (LysMCre-DicerWT) a high cholesterol diet (HCD) for 3 months. Dicer deletion in myeloid cells was confirmed in bone marrow-derived macrophages isolated from LysMCre-Dicerflox mice by real-time PCR. The lipid deposition in the aortas was increased by 50% in LysMCre-Dicerflox (3.3±0.3%) compared to LysMCre-Dicerwt mice (2.1±0.3%) (p = 0.01, n = 13). The differential blood counts and the serum cholesterol and triglyceride levels were not altered between two groups. We found that 79 miRs, including those highly expressed in macrophages (e.g., miR-146a and miR-223), were down-regulated in LysMCre-Dicerflox aortas compared to controls after 3 months of a HCD (p &lt; 0.05, n = 3) using a miR real-time PCR array. In aortas from LysMCre-Dicerflox mice, 471 genes were up-regulated as determined by whole-genome gene expression profiling using Agilent Mouse Microarrays (p &lt; 0.05, n = 3-4). Genes involved in fatty acid and lipid metabolism were enriched among the up-regulated genes as analyzed by GeneGo MetaCore. Up-regulation of Plg, Ptges2, Eci1, Impa2, Acox2, Thrsp, and the lipid droplet-related genes plin-1, -2, -5 and Cidea was confirmed by real-time PCR. Whereas Plg was predicted to be a target of miR-223 by Targetscan, plin-1, -2, and Ptges2 were identified as potential targets of miR-146a using miRanda. These data indicate a protective role of Dicer during atherogenesis by inhibiting lipid metabolism in lesional macrophages through miRs. Thus, regulation of the lipid metabolism in macrophages might be a critical step in the development of atherosclerosis.
Abstract 11181: Late Outcomes Following Bridge-use of Stent-Graft for Blunt Traumatic Aortic Injury in the Younger Patients
Authors: Takuro Tsukube, Tomonori Haraguchi, Yasushi Okada, Chikashi Nakai, Shinichi Nakayama, Takeki Mori
Journal: Circulation (2016)

Introduction: Thoracic endovascular aortic repair (TEVAR) for the younger patients remains controversial because of anatomical characteristics of the aortic arch in youth. We have performed TEVAR as an initial treatment for traumatic aortic injury (TAI) complicated with multiple organ injuries. This study evaluated the early and late outcomes of the younger patients with this approach. Methods: Between 9/03 and 5/16, 56 patients with TAI were treated surgically, including 37 patients underwent TEVAR, 9 underwent open aortic repair (OAR), and 10 required emergent room thoracotomy (ERT), as an initial treatment. The mean age of the patients was 53.6 (SD 19.7) y/o, including 17 patients of younger patients (age under 40 y/o). The mean injury severity score (ISS) was 51.8 (SD 19.8), site of aortic injury was isthmus in 51 patients, and mode of injuries included motor vehicle crashes in 43 and falls in 13. Open aortic repair was selected if multiple organ injuries were not involved or if TEVAR was not suitable due to difficult anatomy of arch branch vessels, and ERT was performed as salvage surgery. Results: Mortality of TEVAR, OAR, ERT group was 13%, 25%, 100%, respectively. In TEVAR group, removal of the stent-graft and secondary OAR were undertaken in 22% (8/37) due to graft malfunctions. Mean time interval from TEVAR to secondary OAR was 39.5 days, and none of the patient died postoperatively. Incidence of secondary OAR was significantly higher in the younger patients (44%, 7/16) when as compared with patients over 40 y/o (2.5%, 1/40). Overall, in the younger patients, OAR was eventually undertaken in 75% (12/16), including 5 as an initial treatment and 7 as the secondary treatment. The mean follow-up periods were 61.5 (SD 25.1) months. Of 45 patients in TEVAR and OAR groups, cumulative survival rate was 78.8% in 5 years, and freedom from aortic event was achieved in 70.8% in 5 years. Conclusions: TEVAR is a safe and effective procedure as an initial treatment of TAI with multiple organ injuries. In the younger patients, TEVAR is recommended as a bridge-use to the secondary open aortic repair.
Abstract 18028: [18F]-fluorodeoxyglucose is a Stronger Correlate of Intraplaque Inflammatory Burden in Human Carotid Plaque Than C-Reactive Protein: A Sub-Study of the Canadian Atherosclerosis Imaging Network (CAIN)
Authors: Myra S Cocker, J David Spence, Robert Hammond, Brian Mc Ardle, Jordan Bernick, Rob deKemp, Cheemun Lum, George Youssef, Yulia Yerofeyeva, Tigran Karavardanyan, Adebayo Adeeko, Andrew Hill, Sudhir Nagpal, Grant Stotts, Jennifer Renaud, Cathy Kelly, Joanne Brennan, Linda Garrard, Murad Alturkustani, Laura Hammond, Jean DaSilva, Jean-Claude Tardif, Rob Beanlands
Journal: Circulation (2013)

Background and Purpose: Inflammation triggers and contributes to the progression of atherosclerosis. C-reactive protein (CRP), a circulating marker of inflammation, is a putative risk factor for cardiovascular disease, but this is not borne out in Mendelian randomization studies. Inflammation in carotid arteries can be imaged with hybrid [18F]-fluorodeoxyglucose (18FDG) positron emission tomography (PET) computed tomography (CT) imaging. In this investigation, circulating levels of CRP and 18FDG uptake in carotid vasculature were directly compared with intraplaque inflammatory burden, using macrophage-specific CD68 immunohistology. Methods: Nineteen prospectively recruited patients (66 ± 11 years, 15 male) scheduled for carotid endarterectomy underwent 18FDG-PET and CT angiography of carotids. CRP levels were assessed. Maximum 18FDG uptake in both internal carotids was quantified and normalized to blood (tissue:blood ratio, TBR). Following endarterectomy, excised plaque was fixed, sectioned and immunostained for CD68. CD68 expression was quantified. Results: Carotid endarterectomy was performed in 19 patients; one received a 2 nd carotid endarterectomy due to bilateral disease. The direct burden of inflammation, as quantified by CD68 immunohistology, correlated with maximum 18FDG uptake (r=0.716, p&lt;0.001). There was no evidence of a correlation between CRP and CD68 (r=0.159, p=0.50), nor with maximum 18FDG uptake (r=0.238, p=0.31). Furthermore, 18FDG and CRP are different correlations where FDG is more strongly correlated with CD68 than CRP (p=0.02, Hoteling Williams test). Conclusion: 18FDG uptake is more strongly related to the extent of inflammatory burden within high-risk carotid plaque than CRP. CRP may not be an accurate criterion for assessing vulnerable carotid plaque (based on histopathology nor 18FDG uptake). Prospective outcomes-based trials are needed to establish 18FDG as a direct biomarker of vulnerable carotid plaque.