tbuckley/cabot-search huggingface dataset:
Abstract 9675: Ultrasound and Microbubble-Targeted Delivery of Small Interfering RNA into Primary Endothelial Cells Is More Effective than Delivery of Plasmid DNA
Authors: Lynda J Juffermans, Bernadet D Meijering, Robert H Henning, Leo E Deelman
Journal: Circulation (2011)

Introduction Ultrasound and microbubble-targeted delivery (UMTD) is a promising non-viral technique for genetic-based therapy. Recently, we demonstrated that with UMTD employing low-intensity ultrasound small dextran molecules enter endothelial cells through transient pores, while the entry of larger dextrans was dependent upon endocytosis. Extrapolating these findings to UMTD of therapeutic compounds for effective genetic-based therapy, we hypothesized that UMTD employing low-intensity ultrasound is more effective when delivering small interfering RNA (siRNA) than plasmid DNA (pDNA). Methods Red fluorescently-labeled siRNA against housekeeping gene GAPDH, pDNA encoding GAPDH, and red fluorescently-labeled pDNA encoding green fluorescent protein (GFP) were delivered into primary bovine aortic endothelial cells using ultrasound (1 MHz, 0.22 MPa) and SonoVue microbubbles. Cellular localization and GFP expression were determined using fluorescent microscopy. The effect of siRNA and pDNA delivery on GAPDH protein levels was determined by western blotting. Results UMTD of siRNA transfected 97.9±1.5% of the cells, with labeled siRNA localized homogenously in the cytoplasm directly after ultrasound exposure. Whereas UMTD of pDNA resulted in only 43.0±4.2% transfected cells, with localization mainly in vesicular structures, co-localizing with endocytosis markers clathrin and caveolin. Delivery of siRNA decreased GAPDH protein levels to 24.3±7.9% of non-treated controls (p&lt;0.01, n=5). In contrast, 24h after delivery of pDNA no increase in GAPDH protein levels could be detected. Transfection efficiency, verified with red fluorescently-labeled pDNA encoding GFP, showed that of the transfected cells only 2.0=0.7% expressed the transgene. Conclusions The localization of small RNA and large DNA molecules after UMTD employing low-intensity ultrasound is an important determinant for the effectiveness of these two genetic-based technologies, as the target for siRNA is located in the cytosol, but for pDNA to be transcribed it needs be in the nucleus. In conclusion, this compartmentalization of therapeutic compounds should be taken into account when designing new genetic-based therapies with UMTD.
Abstract 9001: Transcatheter Aortic Valve Implantation Reduces Neither 30-day nor Midterm Mortality Over Aortic Valve Replacement in High-risk Patients: A meta-analysis of Randomized and Adjusted Observational Studies
Authors: Shin-nosuke Goto, Hisato Takagi, Kotaro Iwata, Hirotaka Yamamoto, Takuya Umemoto
Journal: Circulation (2012)

Background: Our preliminary meta-analysis suggests that transcatheter aortic valve implantation (TAVI) may not reduce 30-day mortality rate over surgical aortic valve replacement (AVR) in high-risk patients with severe aortic stenosis (AS). We performed an updated formal meta-analysis of TAVI versus AVR for reduction of not only early but also late all-cause mortality in AS. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials weresearched through February 2012. Eligible studies were randomized controlled trials or adjusted observational comparative studies of TAVI versus AVR enrolling individuals with AS and reporting 30-day and/or ≥6-month all-cause mortality as an outcome. Odds ratios (ORs) and/or hazard ratios (HRs) with 95% confidence intervals (CIs) (adjusted ORs and/or adjusted HRs in case of observational studies) were abstracted from each individual study. Results: Only one randomized controlled trial and 11 adjusted observational comparative studies enrolling 4134 patients with severe AS were identified. Pooled analysis suggested no significant difference in both 30-day (OR, 0.85; 95% CI, 0.64 to 1.13; P =0.26) and midterm total mortality (HR, 0.99; 95% CI, 0.83 to 1.20; P=0.96; Figure) among patients assigned to TAVI versus AVR. Exclusion of any single study from the analysis did not substantively alter the overall result of our analysis. There was no evidence of significant publication bias. Conclusions: We found that, based on a meta-analysis of data on &gt;4000 patients from 12 studies, TAVI is likely ineffective in reduction of both 30-day and midterm all-cause mortality in high-risk patients with AS.
Abstract 19819: Genetic Pre-Participation Screening in Selected Athletes: A New Tool for the Prevention of Sudden Cardiac Death?
Authors: Giulia Frisso, Giuseppe Limongelli, Riccardo Assorgi, Cristina Mazzaccara, Angela Cordella, Nicola Detta, Antonello D'Andrea, Silvio Romano, Maria Penco, Antonio Pelliccia, Francesco Salvatore, Raffaele Calabrò
Journal: Circulation (2012)

Background: Sudden cardiac death (SCD) of athletes is a topical issue. Borderline cardiac abnormalities may result in SCD, which in turn may be genetically based; thus, genetic analysis may help to identify potentially pathological cardiac abnormalities. Aim: We performed phenotype-guided genetic analysis in athletes who, pre-participation, showed ECG and/or Echo borderline abnormalities, to discriminate subjects at a greater risk of SCD. Subjects and Methods: We studied 24 elite athletes referred by the National Federation of Olympic Sports; and 25 subjects seeking eligibility to practice agonistic sport referred by the Osservatorio Epidemiologico della Medicina dello Sport, Regione Campania. Inclusion criteria were: a) borderline ECG repolarization abnormalities; b) benign ventricular arrhythmias; c) LVWT in the grey zone of physiology versus pathology (MWT 12-15 mm in females; 13-16 mm in males). Based on the suspected phenotype, we screened subjects for LMNA gene, 8 sarcomeric genes, 5 desmosomal genes, and cardiac calcium, sodium and potassium channel disease genes. Results: Genetic analysis was completed in 37 out of 49 athletes, 22 competitive and 27 non-competitive athletes, showing borderline clinical markers suggestive of hypertrophic cardiomyopathy (HCM n 24), dilated cardiomyopathy (n 4), arrhythmogenic right ventricular dysplasia/catecholaminergic polymorphic ventricular tachycardia (ARVD/CPVT n 11), long QT syndrome (LQTS n 4), sick sinus syndrome (SSS n 5), or Brugada syndrome (BrS n 1). We identified 11 mutations in 9 athletes (an ARVD athlete was a compound heterozygote for the PKP2 gene and an HCM athlete was a double heterozygote for the MYBPC3 and TNNT2 genes): 3 known mutations related to LQTS, HCM and ARVD, respectively, and 8 novel mutations, located in the SCN5A, RyR2, PKP2, MYBPC3 and ACTC1 genes. The new mutations were absent from ∼800 normal chromosomes and were predicted probably damaging by in silico analysis. Patch clamp analysis in channelopathies indicated that some mutations were associated with abnormal biophysical behavior of the corresponding mutant protein. Conclusion: Genetic analysis may help distinguish between physiology and pathology in athletes with suspected familial or sporadic heart disease.
Abstract 8377: Cathepsin K Deficiency Suppresses the Development of Experimental Intimal Hyperplasia in Response to Injury
Authors: Lina Hu, Xian Wu Cheng, Guo-Ping Shi, Haizhen Song, Kazumasa Unno, Haiying Jiang, Kenji Okumura, Toyoaki Murohara, Masafumi Kuzuya
Journal: Circulation (2011)

Background. Cathepsin K (Cat K), a potent elastinolytic and collagenolytic cysteine protease, is considered likely to participate in the development and destabilization of atherosclerotic plaques. In order to define the role of Cat K in arterial remodeling, we evaluated the influence of the targeted deletion of the Cat K gene (Cat K−/−) on vascular remodeling after flow cessation in murine carotid arteries. Methods and Results. Male Cat K+/+ and Cat K−/− mice receiving normal chow underwent ligation or ligation/polyethylene cuff-placement injuries to the left common carotid artery just proximal to its bifurcation, and were then processed for morphological and biochemical studies at specific time points. There were no changes in the expression of Cat K mRNA or protein in the basal or injured arteries. Histological analysis revealed that there was significantly less intimal hyperplasia in Cat K−/− mice than in control mice at 28 days after surgery. At Day 4 after surgery, the amounts of mRNA for MMP-9, MMP-14, toll-like receptor-4 (TLR-4), chemokine ligand 12 (CCL12) and the contents of macrophages were significantly lower in both the single- and double-injured arteries of Cat K−/− mice than in corresponding model of Cat K+/+ mice. At Day 7, gelatin zymography showed that MMP-9 activity increased in the injured arteries of both types in Cat K+/+ mice. An ex vivo migration assay showed that Cat K deficiency impaired smooth muscle cell migration from aortic explants. Although there were no differences in SMC adhesion or apoptosis in mice of either genotype, Cat K deficiency impaired chemoattractant-directed SMC and macrophage invasions. Synthetic cathepsin inhibitor E64d inhibited ligation-induced neointima formation in Cat K+/+ mice but a deficiency of endogenous inhibitor cystatin C deteriorated the neointima in apoliporotein E deficiency mice. ELISA demonstrated that Cat K−/− mice had lower levels of plasma stromal-derived factor-1 and interleukin-1β. Conclusions. This study demonstrates an essential role of Cat K in atherosclerotic lesion formation in response to injury, possibly via the reduction of inflammation and SMC formation, suggesting a novel therapeutic strategy for the control of atherosclerosis by regulating Cat K activity.
Abstract 8165: The Association of Vascular Calcification and All Cause Mortality in Diabetes: Diabetes Heart Study
Authors: Subhashish Agarwal, David M Herrington, Amanda J Cox, Timothy M Morgan, Jianzhao Xu, John J Carr, Barry I Freedman, Donald W Bowden
Journal: Circulation (2011)

Background Coronary artery calcium (CAC), carotid artery calcium (CAAC), and abdominal aorta calcium (AAC) are noninvasive measures of atherosclerosis that predict mortality and are increasingly being utilized in risk prediction models. In a prior study we demonstrated that CAC is a powerful independent factor for mortality in type 2 diabetes affected subjects with odds of death six fold higher in CAC greater than thousand compared to CAC lower than ten. The objective of the current study was to determine which vascular bed is a better predictor of mortality in diabetes. Methods A total of 854 participants, ages 39-86, with complete data on diabetes, vascular imaging and covariates in the Diabetes Heart Study (DHS) were followed for an average of 7.4 years. Atherosclerosis imaging was performed utilizing fast-gated helical computed tomography scan at baseline to obtain measures of coronary, carotid, and abdominal aorta Agatston calcium scores. Seven-year risk estimates for all-cause mortality were obtained using logistic regression models adjusted for age, gender, smoking, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity including log transformed (CAC+1), (CAAC+1), and (AAC+1). Results Overall, 15% (129/854) of participants died during follow-up. Coronary artery calcium was associated more strongly than either carotid or abdominal calcium with mortality. After adjusting for potential confounders, and each other (CAC, CAAC, and AAC), the odds ratio of all-cause mortality increased 2.08 fold (95% CI, 1.46-3.01) for each 1-standard deviation (SD) increment of log transformed CAC score, 1.38 fold (95% CI, 1.02-1.89) for each 1-SD increment of log CAAC, and 0.9 fold (95% CI, 0.60-1.40) for each 1-SD increment of log AAC. A receiver operating characteristic curve analysis also suggested that CAC score was a better predictor of mortality than was CAAC and AAC, with areas under the curve of 0.77, 0.76, and 0.75, respectively. Conclusion Atherosclerosis imaging is becoming widely available and is now utilized to predict future risk for clinical events. This study found that CAC score is a better predictor of mortality than carotid or abdominal aorta vascular beds in diabetes.
Abstract 225: Incidence, Timing and Effect of Fever on Outcomes Following Resuscitation from Cardiac Arrest
Authors: Kory Gebhardt, Francis X Guyette, Ankur Doshi, Clifton Callaway, Jon C Rittenberger
Journal: Circulation (2012)

Background Fever after cardiac arrest is associated with poor outcomes. We hypothesized that the association of fever and outcome would differ between patients treated with therapeutic hypothermia (TH) and those not. Methods We included 338 comatose patients who survived &gt;48 hours after admission to a single center between 1/1/2005 and 6/30/2010. Fever was defined as T≥ 38.0°C within 48 hours of arrest. Categories of post-cardiac arrest illness severity were defined by neurological examination and sequential organ failure assessment (SOFA) score on presentation: 1) awake, 2) coma (not following commands but intact brainstem responses) + mild cardiopulmonary dysfunction (SOFA cardiac + respiratory score &lt;4), 3) coma + moderate-severe cardiopulmonary dysfunction (SOFA cardiac + respiratory score &gt;=4), and 4) coma without brainstem reflexes. Logistic regression measured association of fever and clinical variables with survival and good outcome (discharge to home or to acute rehabilitation facility). Results Mean age was 60 years (SD 16), 212(63%) had out-of-hospital cardiac arrest (OHCA), and 220 (65%) received TH. Ventricular fibrillation/ventricular tachycardia (VF/VT) was the primary rhythm for 133 (40%). Post arrest illness severity was category II in 119 (38%) , category III in 62 (20%), and category IV in 133 (42%). One hundred twenty eight (38%) survived; 75 (22%) with good outcomes. Fever was present in 142 (42%) of patients, with a median onset of 15 hours post-arrest in the non-TH cohort and 36 hours in TH cohort. Survival was associated with VF/VT (OR 2.60, CI 1.56-4.32) and category IV (OR 0.15, CI 0.08-0.27). Good outcome was associated with OHCA (OR 4.08, CI 1.99-8.39) and category IV (OR 0.13, CI 0.06-0.27). Fever was not associated with survival (OR 0.99, CI 0.57;1.70) or good outcome (OR 0.90, CI 0.47; 1.75) overall. Fever was negatively associated with survival in non-TH cohort (OR 0.38, CI 0.17;0.84) but not within the TH cohort (OR 1.48, CI 0.73; 2.97). Fever was not associated with good outcomes in the TH cohort (OR 1.34, CI 0.59; 3.06) or non-TH cohort (OR 0.36, 0.11; 1.13). Conclusions Fever is common in both TH and non-TH patients. Onset time is later after TH. Fever is negatively associated with survival in non-TH patients but not in TH patients.
Abstract 289: Use of Epinephrine During In-Hospital Cardiac Arrest May Not Increase Rate of Survival to Discharge
Authors: Antoine R Trammell, Tze-chun V Liao, Prasad Abraham, Tara Holt, Benjamin Renelus, Shikha Sharma, Abarmard M Zafari
Journal: Circulation (2012)

Introduction: In a recent large observational resuscitation study the use of epinephrine during out-of-hospital cardiac arrest was associated with survival to hospital admission but not with survival to discharge. Few studies have studied the impact of epinephrine on in-hospital survival outcomes. This study examines in-hospital cardiac arrest survival and the use of epinephrine. Hypothesis: The use of epinephrine during in-hospital cardiac arrest is associated with increased code survival and survival to discharge. Methods: This retrospective and observational study includes 286 cases of in-hospital cardiac arrest wherein epinephrine was administered. The outcomes were code survival and survival to discharge. The study period was between June 2010 and October 2011 at an urban, academic medical center. Resuscitation characteristics, including use of epinephrine were compared between code survivors and non-survivors. Charlson comorbidity scores were used to adjust the severity of illness for both groups. Chi-square was used for hypothesis testing. Results were considered significant for p-values &lt; 0.05. Results: Epinephrine was used in 272 cases of in-hospital cardiac arrest. In 55% (n = 136) of the study cohort, only one dose of epinephrine was administered. There is a significant association between the use of epinephrine and code survival (X2 = 9.87, p = 0.0017). There is a statistically significant association between the use of epinephrine and not surviving to discharge (X2 = 7.69, p = 0.0056). Among persons receiving epinephrine, 13.6% (n = 37 of 272) survived to hospital discharge. There is no significant association between the initial rhythm and code survival (X2 = 75.36, p = 0.34) or survival to discharge (X2 = 4.56, p = 0.47) when epinephrine was administered. The median Charlson score for both groups was 4 (IQR = 2 to 6) and is not significantly different (Ws = 10955, z = 1.24, p = 0.21). Conclusions: Epinephrine administration during in-hospital cardiac arrest is associated with code survival, but not survival to discharge. Our observations are consistent with the findings reported regarding epinephrine use in out-of-hospital cardiac arrest but warrant larger, randomized studies to confirm our findings
Abstract 8846: Relationship Between Left Appendage Volume and Function, and Left Atrial Function: A Real-Time Three-Dimensional Transesophageal Echocardiography Study
Authors: Yoko Fukuoka, Masaki Izumo, Takeji Saitoh, Eiji Kuwahara, Jun Tanaka, Swaminatha V Gurudevan, Kirsten Tolstrup, Robert J Siegel, Takahiro Shiota
Journal: Circulation (2011)

Background: Left atrial appendage (LAA) has multilobed complicated structure. Therefore, attempts to quantitate LAA size and function by 2-dimensional (2D) methods may not offer acurate evaluations. Recent development of real-time 3-dimensional transesophageal echocardiography (RT3D-TEE) has enabled us to examine morphology and to determine absolute volumes of LAA without geometrical assumptions. The association between LAA volume and function, and left ventricular (LV) and left atrial (LA) function has not been well investigated. Methods: Eighty-nine pts who underwent RT3D-TEE for evaluation of thrombus in LAA were studied. All measurements were performed off-line software. LAA maximal (max) orifice area, max and minimal (min) volumes, and ejection fraction (LAAEF) were assessed (Figure). LAA emptying flow velocity was also measured. We determined max and min LV and LA volume (LAV) by the Simpson method with 2D transthoracic echocardiography. LAV total emptying fraction (LAEF) was determined as (max LAV - min LAV)/ max LAV. Similarly in pts with sinus rhythm, active and passive LAEF were calculated. Pulsed Doppler E, tissue Doppler E' and E/E' were also measured. Additionally, as a parameter of LA compliance, we measured time velocity integral of systolic pulmonary venous flow (SVTI). Results: LAA volume was significantly correlated with max LAV, min LAV, E/E' and SVTI. LAAEF was significantly correlated with age, all LAEFs, E/E' and SVTI. There was no correlation between LAA volume and LAAEF (Table). Multiple regression analysis revealed that max LAV and E/E' (both, p&lt;0.01) were independently correlated with 3D derived LAA volume, and active and passive LAEF were independently correlated with 3D derived LAAEF (p=0.02 and p=0.05, respectively). Conclusion: LAA volume determined by RT3D-TEE was independently associated with E/E' and max LA volume. Moreover, LAA function was independently associated LA function.
Abstract 8572: Enhanced Angiogenesis By Transplantation Of iPS Cell-derived Flk-1 <sup>+</sup> Cell Sheet Created By A Novel Magnetic Tissue Engineering Method
Authors: Tetsutaro Kito, Rei Shibata, Hirohiko Suzuki, Masakazu Ishii, Takashi Yamamoto, Yasushi Numaguchi, Toyoaki Murohara
Journal: Circulation (2011)

Background: Therapeutic angiogenesis using cell transplantation represents a novel strategy for severe ischemic diseases, but some patients had poor response to angiogenic cell therapy. Therefore, alternative cell source and cell application strategy have been extensively searched. Induced pluripotent stem cells are expected as one of powerful tools for regenerative medicine. We investigated a therapeutic potential of iPS cell sheet created by a novel magnetite tissue engineering technology for reparative angiogenesis. Methods and Results: Flk-1 + cells, as a vascular progenitor marker were induced from mouse iPS cells after 5 day of culture. Flk-1 + cells were purified by FACS sorting, and these cells differentiated into CD31 + endothelial and α-SMA + smooth muscle cells. Sorted Flk-1 + cells incubated with magneticnanoparticle-containing liposomes (MCLs) were cultured. MCL-labeled Flk-1 + cells were mixed with diluted extracellular matrix (ECM) precursor, and a magnet was placed on the reverse side. Magnetized iPS cell-derived Flk-1 + cells formed multilayered cell sheet after 24h incubation period. Nude mice were subjected to unilateral hind limb ischemia and separated into 3 groups. The constructed Flk-1 + cells- or Flk-1 − cells- sheet placed on the ischemic adductor muscles using the Alnico magnet before skin closure. For the control group, ECM precursor gel was layered onto the ischemic tissues. Blood flow recovery and the extent of angiogenesis were assessed by a laser doppler blood flowmetry and capillary density. The Flk-1 + cell sheet group had a greater angiogenesis in ischemic tissues compared to the control and Flk-1 − cells sheet groups (p&lt;0.05). The angiogenic and tissue-preserving effects of Flk-1 + cell sheets were attributable to an increased expression of VEGF mRNA in ischemic tissues. We did not detect formation of any tumors in Flk-1 + cells, but not in Flk-1 − cells, transplanted mice at least until post-operative day 60. Conclusions: Implantation of iPS cell-derived Flk-1 + cells has augmented ischemia-induced angiogenesis. iPS cell-derived Flk-1 + cell sheet created by the novel magnetic nanoparticle-based tissue engineering technology would represent a new modality for therapeutic angiogenesis and tissue regeneration.