tbuckley/cabot-search huggingface dataset:
Abstract 18155: Wnt10b Promotes Cardiac Functional Recovery After Infarction Through Stimulation of Coronary Vessel Formation and Cardiomyogenesis
Authors: David T Paik, Meena Rai, Sergey Ryzhov, Igor Feoktistov, Antonis K Hatzopoulos
Journal: Circulation (2013)

We previously showed that the canonical Wnt signaling ligand Wnt10b is strongly induced in mouse hearts one week after infarction during the initial stages of cardiac tissue repair. Wnt10b regulates cell fate decisions in various organs, but its role in the heart is unknown. Using histological and molecular analyses, we discovered that Wnt10b is normally expressed in cardiomyocytes and stored in the intercalated discs. One week after coronary artery ligation, Wnt10b is strongly and specifically induced in cardiomyocytes surrounding the infarct zone. To determine the role of Wnt10b in cardiac repair, we generated a new mouse transgenic line to enhance the levels of endogenous Wnt10b expression in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the infarct zone, reduced scar size, and improved ventricular function compared to wild-type mice. Wnt10b stimulated Vascular Endothelial Growth Factor Receptor 2 (Vegfr-2) in endothelial cells and Angiopoietin-1 in smooth muscle cells through NF-kB activation. These effects coordinated endothelial growth and pericyte recruitment, thus promoting the formation of large, coronary-like blood vessels. Enhanced neovascularization and reduced fibrosis was accompanied by formation of cardiomyocyte islands within scar tissue, suggesting that Wnt10b promoted myocardial regeneration. Taken together, our results indicate that Wnt10b is a physiological regulator of coordinated formation of blood vessels and myocardial regeneration in the injured heart. Our findings could lead to novel effective strategies to optimize the inherent reparative and regenerative capacities of the heart in order to prevent the onset of heart failure after myocardial infarction.
Abstract 18435: Normal Body Mass Index Does Not Protect From Coronary Atherosclerosis in the Metabolic Syndrome
Authors: Jaime P Almandoz, Benjamin L Willis, Jennifer E Lambert, Scott M Grundy, Laura F DeFina
Journal: Circulation (2013)

Background: Obesity is a known risk factor for coronary atherosclerotic disease, but epidemiological data suggest that it may not additionally contribute to mortality in people with the metabolic syndrome (MetS). We hypothesized that people with normal weight (NW) plus MetS are at greater likelihood for having coronary artery calcium (CAC) than NW without MetS and are as likely to have CAC as those with MetS who are overweight (OW) and/or obese (OB). Methods: We evaluated CAC scores (by Agatston units) from computed tomography scans in 11,621 men, age 40-80 years, with no history of CAD from the Cooper Clinic Longitudinal Study. Subjects were divided into 6 groups according to BMI class (NW 18.5-24.9; OW 25-29.9; OB &gt;30 kg/m 2 ) and the presence of MetS defined by 3 or 4 metabolic risk factors, exclusive of obesity: BP &gt;130/85 mmHg, glucose &gt;100 mg/dL, triglycerides &gt;150 mg/dL, and HDL-C &lt;40 mg/dL. We summarized levels and prevalence of CAC and tested for trends across obesity levels using multiple logistic regression analyses, adjusting for age and smoking. Results: The prevalence CAC &gt;0 in the study population was 55.5%. The table shows median CAC score (Agatston units), CAC &gt;0 prevalence (%), and odds ratios (OR) for CAC &gt;0 and CAC &gt;100 by logistic model, adjusted for age and smoking, in the six groups. The marginal trend in prevalence of CAC &gt; 0 across BMI groups is significant (p=0.01); however, the trend difference between those with and without MetS is not significant (p=0.773). The group with NW plus MetS has a prevalence of CAC comparable to those with OB plus MetS. Conclusion: In persons with or without MetS the likelihood of CAC increases with BMI. Those with MetS are more likely to be OW or OB. However, NW persons with MetS appear as likely to have detectable and clinically significant CAC, or a high odds ratio for CAC, as the OW and OB with MetS. Being NW does not protect against CAC in people with MetS.
Abstract 9941: Prior Myocardial Infarction is Associated with Endothelial Dysfunction in Women with Microvascular Coronary Dysfunction
Authors: Megha Agarwal, Kamlesh Kothawade, Chrisandra Shufelt, Greg Lentz, Puja Mehta, Tara L Sedlak, Margo Minissian, Zachary Hobel, Saibal Kar, Babak Azarbal, Bruce Samuels, C. Noel Bairey-Merz
Journal: Circulation (2012)

Background: Patients with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) often have microvascular coronary dysfunction (MCD). MCD is associated with an elevated risk of myocardial infarction (MI), yet the pathophysiological mechanism(s) are not well understood. We compared endothelial-dependent and endothelial-independent pathways in women with MCD with and without a prior history of MI. Methods: 67 women with persistent chest pain, clinical evidence of myocardial ischemia, and no obstructive CAD by angiography, underwent clinically-ordered coronary reactivity testing, which included infusion of intracoronary acetylcholine (ACH), adenosine and nitroglycerin to determine percent change in coronary artery diameter and flow. History of prior MI was obtained through supervised, self-reported questionnaire and confirmed with medical record evidence of elevated troponin when available. Data were analyzed using a Wilcoxon signed-rank test. Results: Overall 10 (15%) women (51±12 years) had a history of MI (4 confirmed by available medical records) and 57 (55±9 years) had no prior MI (No-MI). There were no group differences in rates of age, hypertension, dyslipidemia, body mass index, smoking history, family history of heart disease, or diabetes (data not shown). Intracoronary ACH response (endothelial-dependent pathway) was significantly lower in the group with prior MI compared to no-prior MI group (figure). Measurements of coronary flow reserve with adenosine infusion and coronary vasodilation with nitroglycerin infusion (both endothelial-independent pathways) were not different between groups. Conclusions: Prior MI in women with MCD is associated with endothelial dysfunction. Future study should consider coronary endothelial dysfunction as a MCD treatment target in women with a history of MI and no obstructive CAD.
Abstract 14447: Dose Response Effect of Cigarette Smoking on Cardiac Function and Heart Failure in the Multi-Ethnic Study of Atherosclerosis
Authors: Ola Gjesdal, Nathan Mewton, Kihei Yoneyama, Colin Wu, Natl Heart, David Jacobs, Stephen Sydney, Cora E Lewis, Kiang Liu, David A Bluemke, Joao A Lima
Journal: Circulation (2012)

Ola Gjesdal, 2012 Finalist and Presenting Author
Abstract 9917: Electrical Coupling and Action Potential Properties of Transplanted Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Comparison with Fetal Cardiomyocytes
Authors: Marcel Halbach, Gabriel Peinkofer, Sven Baumgartner, Martina Maaβ, Benjamin Krausgrill, Dennis Ladage, Azra Fatima, Tomo Saric, Júrgen Hescheler, Jochen Múller-Ehmsen
Journal: Circulation (2012)

A functional integration and maturation of transplanted cardiomyocytes prevents arrhythmias and enhances synergistic contractions of transplanted and host tissue. We compared electrical coupling and action potential (AP) properties of transplanted induced pluripotent stem cell-derived cardiomyocytes (iPSCM), which are regarded as promising cell type for cell therapy, and fetal cardiomyocytes (FCM). Methods: Murine iPSCM expressing eGFP and a puromycin resistance under control of the α-MHC promoter, were purified by antibiotic selection and dissociated at day 16 of differentiation. FCM from transgenic mice expressing eGFP under control of the α-actin promoter were isolated at day 13.5-15.5 p.c. IPSCM and FCM were injected into adult mouse hearts (2 injections, ∼500,000 cells per site). 6-12 days after transplantation, recipients were sacrificed and viable ventricular tissue slices (thickness: 150 μ m) were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue. AP recordings were performed by glass microelectrodes in transplanted cells, which could be identified by their green fluorescence, and in neighboring host tissue within the slices. Results: Coupling of iPSCM and FCM to host tissue could be clearly demonstrated, 74% of iPSCM and 85% of FCM were coupled. Some transplanted iPSCM and FCM had no conduction blocks even at high stimulation frequencies up to 8 Hz, while others had blocks at lower frequencies. The delay between stimulus and AP upstroke was significantly longer in iPSCM (35.34±8.79 ms) than in FCM (19.84±3.77 ms). In host tissue, the delay was 6.96±1.0 ms. IPSCM had immature AP properties at all time points, while FCM matured and possessed comparable AP properties as host cardiomyocytes after 12 days. Conclusions: IPSCM and FCM are able to integrate electrically into host tissue, but conduction blocks and decelerations occur. The quality of integration is higher in FCM than in iPSCM. AP properties of transplanted iPSCM differ considerably from those of host cardiomyocytes up to day 12 after transplantation, while FCM mature to an adult electrophysiological phenotype.
Abstract 9857: Cardiac Function in an Extraordinarily Long-lived Rodent, the Naked Mole-rat
Authors: Kelly M Grimes, Ying Ann Chiao, Merry L Lindsey, Rochelle Buffenstein
Journal: Circulation (2012)

Mechanisms underlying prolonged maintenance of cardiac function in long-lived species may differ from those involved in short-lived species. We assessed cardiac function in young (2-4 year old) male and female naked mole-rats (NMRs; Heterocephalus glaber) and compared these data to those of young (7-8 month old) male and female C57BL/6 mice to establish the use of the NMR for cardiac aging studies. NMRs have a maximum lifespan potential of 32 years (8-fold longer than mice) despite being comparably sized. Furthermore, NMRs maintain good health for at least 75% of their extremely long lifespan, equivalent to &gt;80 year old humans. As such, NMRs provide us a unique opportunity to explore mechanisms that enable prolonged maintenance of cardiac function. Like humans NMRs have a lower than predicted heart rate for their body size. Interestingly, unlike in mice, isofluorane anesthesia had little depressive effect on NMR cardiac function, as heart rates stayed similar between anesthetized and unanesthetized NMRs. Echocardiography revealed significant differences between species (see table). While there were no species differences in average diastolic wall thickness, average systolic wall thickness was greater in mice compared to NMRs. Baseline fractional shortening (FS) was significantly lower in NMRs than in mice. Dobutamine stress echocardiography (3 μg/g body weight i.p.) elicited a greater increase in FS in NMRs than in mice, suggesting that NMRs have greater cardiac reserve. Doppler analysis of blood flow revealed that diastolic (E/A ratio) and systolic (aortic peak velocity) function were significantly different between species. The higher NMR E/A ratio is indicative of more pliable ventricle muscle and less reliance on atrial filling. The interspecies differences observed may indicate mechanisms employed by NMRs to prolong cardiac health into old age. Future studies will probe the existence of such mechanisms and investigate age-related cardiac changes in NMRs.
Abstract 18662: Frequency and Temporal Patterns of Implantable Cardiac Defibrillator Therapies in Patients With Left Ventricular Assist Devices
Authors: Jason Appelbaum, Ramal Weragoda, Michael Lloyd, Jonathan Langberg, Michael Hoskins
Journal: Circulation (2013)

Background: Left ventricular assist device (LVAD) use is becoming increasingly common in patients with end-stage heart failure. These patients are at high risk for ventricular arrhythmias. The pattern of ICD therapies in these patients is not well characterized. Methods: Our single-center retrospective cohort included 86 patients with ICDs and LVADs followed at Emory University Hospital. Data collected included frequency of ICD therapies, type of therapy (appropriate vs. inappropriate; shocks vs. anti-tachycardia pacing (ATP)), and time-course of therapies. Results: 36 patients (42%) received ICD therapy during a mean follow-up period of 13.6 months. There were 105 episodes (2.9 episodes/patient) during which ICD therapies were delivered, with a total of 379 individual arrhythmias treated (3.6 arrhythmias per episode of therapy). 61.4% of therapies were appropriate, 8.4% were inappropriate, and 31.6% were unknown. Of the 79 episodes treated with appropriate therapy, 36 episodes (46%) required ICD shocks, whereas 43 episodes (54%) were treated with ATP alone. Overall, 33% of the total cohort and 81% of patients who received therapy received at least one ICD shock. Twenty-two patients (61%) received therapy between 1-3 times, while the remainder (14 patients, 39%) received therapy 3-10 times. Eighteen (17%) episodes occurred within the first month after LVAD implantation, with 10 (10%) occurring between 1-3 months, 53 (50%) occurring between 3-12 months, and 24 (23%) occurring more than one year after LVAD implantation. Conclusion: Analysis of our LVAD cohort revealed three important findings: 1. ICD therapy is very common (42%) in the first year after LVAD implantation; 2. Ventricular arrhythmias are highly clustered in this cohort; 3. ATP is frequently effective. These findings have important implications on device follow-up and programming for this expanding patient population.
Abstract 18502: Bleeding Post PCI: Predictors of “ANY” Bleeds: Six Month Results from the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) Registry
Authors: Jennifer Yu, Giora Weisz, Bernhard Witzenbichler, Timothy D Henry, Annapoorna S Kini, Thomas Stuckey, David J Cohen, Peter B Berger, Antonio Colombo, Fayaz Shawl, Philippe Gabriel Steg, David Moliterno, James Hermiller, Sylvia Xistris, Socrates Kakoulides, Catherine Cashy, Robert Kulina, Mitchell Krucoff, Georgios Vlachojannis, Samantha Sartori, Roxana mehran
Journal: Circulation (2012)

Introduction. While recent studies have highlighted the clinical importance of minor, or “nuisance” bleeding, the predictors of all bleeding complications including minor bleeding events have not been examined in detail. Methods. The PARIS registry was a multicenter, international, all-comers registry of patients who had undergone successful PCI in 2009-2010 for stable angina, acute coronary syndrome (ACS) or documented silent ischemia. All bleeding events were adjudicated by a Clinical Events Committee according to the Bleeding Academic Research Consortium (BARC) criteria from source documents. We compared baseline clinical and treatment variables in patients who had any versus no bleeding at 6-months. Results. Of 5,033 patients, 235 (4.7%) had a bleeding event in the first 6-months. Of these, 27.7% had BARC type 1 bleeding, 40.4% had BARC type 2 bleeding, 30.2% had type 3, 0.4% had type 4 (CABG-related), and 1.3% had type 5 (fatal) bleeding. Compared to patients with no bleeding, patients who had bleeding were more likely to be older, female, non-smokers, and to be prescribed on warfarin on discharge (Table). After multivariable analysis, independent predictors of 6-month bleeding were age (OR 1.02, 95% CI 1.002 - 1.03), female gender (OR 1.9, 95% CI 1.3 - 2.9), and warfarin therapy (OR 2.6, 95% CI 1.7 - 3.7, all p&lt;0.05), whereas hypertension was associated with reduced risk of bleeding (OR 0.7, 95% CI 0.52 - 0.98, p=0.04). Treatment with prasugrel (vs. clopidogrel) was not a predictor. Conclusion. In this real world, contemporary PCI registry with close evaluation of bleeding events, the 6-month rate of any bleeding was 4.7%. Almost 70% of these bleeding incidents were BARC type 1 and 2, which may be classified as minor or “nuisance” bleeds. Age, female gender, and warfarin were independent predictors of bleeding events. Table.
Abstract 18260: Apolipoprotein A-I Mimetic Peptide, 4F Targets Lipoxygenases via miR193-3p Induction to Rescue Severe Pulmonary Hypertension
Authors: Salil Sharma, Gabe Wong, Soban Umar, David Meriwether, Mohamad Navab, Srinivasa T Reddy, Mansoureh Eghbali
Journal: Circulation (2013)

Background: Pulmonary hypertension (PH) causes increase in pulmonary arterial pressure causing right ventricular (RV) hypertrophy and RV failure (RVF). We have shown that apolipoprotein A-I mimetic peptide 4F rescues advanced PH and decreases circulating levels of oxidized fatty acids [hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids(HETEs)] in the MCT rat-model of PH. Here, we show that 4F rescues PH in rats and mice by inducing miR-193-3p (miR193), which regulates the enzymes responsible for the production of HETEs and HODEs. Methods and results: PH was induced in rats by monocrotaline (MCT, 60mg/kg,s.c. single injection) or in mice by hypoxia (O 2 ≤10%) for 21 days. 4F daily therapy or intratracheal instillation of miR193 were started after the establishment of PH in both models (4F: 50mg/kg/day, s.c. from day 21-30 in MCT model and day 14-21 in hypoxia model; miR193 (20nM) at days 16, 21 and 26 in MCT model or at days 14 and 18 in hypoxia model). RV pressure (RVP) was measured by direct catheterization. Rats developed PH 21 days after MCT (RVP=67.12±1 in PH vs. 29.8±1mmHg in the ctrl group) which progressed to RVF by day 30 (RVP=74±1, p&lt;0.05 vs ctrl). 4F therapy rescued PH in both models (MCT model: RVP=46±3 mmHg, p&lt;0.05 vs PH and RVF; Hypoxia model: RVP=22±3.8 mmHg vs 36.91±5.74 in PH and 20.93±2.52 in ctrl normoxic mice). MicroRNA microarray and qPCR showed a ~3 fold downregulation of miR193 in PH that was normalized to ctrl levels by 4F treatment in both models. OE of miR193 (20nM) resulted in ~2.5 fold gain of miR193 in the lung tissue and rescued preexisting PH as the RVPs were significantly lower than PH group in both models (38.2±5.5 mmHg in MCT-rat and ~25.3±0.97mmHg in hypoxic-mice). MiR193 therapy reversed increased arteriolar muscularization in PH. In vivo gain of miR193 suppressed transcription of lipooxygenases ALOX5, ALOX12 and ALOX15. In vitro treatment of human Pulmonary Arterial SMCs (hPASMC) with HETEs and HODEs suppressed miR193 levels in the absence of 4F. Lastly, miR193 OE decreased hPASMCs proliferation in the presence of serum or 12-HETE (100ng/ml) by &gt;2 folds (p&lt;0.05 vs ctrl) whereas miR193 KD increased proliferation. Conclusion: 4F rescues preexisting severe PH in rats and mice by inducing miR193 and targeting lipoxygenases.
Abstract 18201: Src-Dependent Caveolar Trafficking Defects in Hereditary Pulmonary Arterial Hypertension
Authors: Allison R Prewitt, Sampa Ghose, Andrea Frump, Anne Kenworthy, Mark de Caestecker
Journal: Circulation (2013)

Patients with hereditary pulmonary arterial hypertension (HPAH) inherit heterozygous germ line mutations in the BMP type 2-receptor, BMPR2, but it is not known how these mutations cause the disease. Bmpr2 mutant mice have endothelial dysfunction and increased vascular permeability, and are more susceptible to the development of pulmonary hypertension. In these studies we explore the mechanisms mediating endothelial barrier dysfunction in Bmpr2+/- mice. Conditionally immortalized pulmonary endothelial cells (ciPECs) from Bmpr2+/- mice have increased permeability to 70kD dextran and albumin, but not to 4kD dextran, suggesting that Bmpr2+/- ciPECs have intact cell-cell junctions but increased transcellular (vesicle mediated) permeability. Caveolae are the predominant vesicle involved in transcellular permeability in endothelium. Transmission EM shows an increase in Caveolar structures in ciPECs and intact endothelium of Bmpr2+/- lungs. Quantitative analysis indicates that Caveolin-1 (Cav1) and Cavin have altered localization from the plasma membrane (PM) in wild type ciPECs to an intracellular localization in Bmpr2+/- ciPECs. In addition, inhibition of Caveolar endocytosis with the Dynamin-2 inhibitor, Dynasore, restores Cav1 localization to the PM in Bmpr2+/- PECs, suggesting there is increased Dynamin-dependent Caveolar endocytosis and trafficking in Bmpr2+/- ciPECs. Bmpr2+/- ciPECs also have increased levels of phosphorylated (pY14) Cav1 associated with increased expression of active Src-kinase (pY416), the kinase responsible for phosphorylating Cav1 and initiating Caveolar endocytosis. The selective Src-family kinase inhibitor PP2, reduces pY14-Cav1 and rescues Cav1 and Cavin localization to the PM in Bmpr2+/- ciPECs. Furthermore, PP2 restores endothelial barrier function in Bmpr2+/- ciPECs demonstrated by a reduction in albumin and 70kD dextran permeability. These data demonstrate a defect in Caveolar trafficking mediated by constitutive activation of Src kinase in Bmpr2+/- ciPECs, and suggest Src kinase inhibitors may ameliorate endothelial barrier dysfunction in HPAH patients.
Abstract 18608: Serial Quantitative Coronary Analyses for the Evaluation of One-Year Changes in Grafts and Native Vessels After a Coronary Artery Bypass Surgery: Insights From the Cardiac Catheterization for Bypass Graft Patency Rate Optimization (CABG-PRO) Study
Authors: Anna P Kotsia, Tesfaldet T Michael, Bavana V Rangan, Lampros K Michalis, Dimitris I Fotiadis, Michail I Papafaklis, Shuaib A Abdullah, Jeffrey Hastings, Jerold M Grodin, Subhash Banerjee, Emmanouil S Brilakis
Journal: Circulation (2013)

Background: Left internal mammary arteries (LIMAs) and saphenous vein grafts (SVGs) are widely used for coronary artery bypass surgery (CABG), but there is limited information on the post-CABG remodeling of these vessels, as well as the bypassed native coronary arteries. We aimed to investigate the serial changes in lumen dimensions of SVGs, LIMAs and the bypassed native arteries in humans. Methods: Thirteen consecutive patients with recent CABG enrolled in our study and underwent angiography immediately after the surgery and one year later. Quantitative coronary analysis (using CAAS Workstation 5.11 software) was performed in 12 LIMAs, 26 SVGs and 59 native coronary arteries that were bypassed. Results: Mean age was 60.8±5.8 years and all the study patients were men while the initial clinical presentation was stable angina (76.9%). Compared to immediately post CABG, at 12 month follow-up angiography the minimal, maximal and mean SVG lumen diameters of the SVGs significantly decreased: (2.83±0.87mm vs 1.99±0.79mm, p&lt;0.0001; 5.10±1.52mm vs 3.82±1.20mm, p&lt;0.0001; 3.96±1.22mm vs 2.75±0.97mm, p&lt;0.0001; respectively). No significant differences were observed in the baseline and follow-up measurements of LIMA grafts (minimal lumen diameter 1.31± 0.78mm vs 0.86±0.72mm, p=0.17; maximal lumen diameter 2.74±1.25mm vs 2.28mm±1.52, p=0.31; mean lumen diameter 0.62±0.45mm vs 1.02±1.12mm, p=0.24) and the native coronary vessels (minimal lumen diameter 0.76±0.40mm vs 0.82±0.46mm, p=0.31; maximal lumen diameter 2.88±0.99mm vs 3.07±1.18mm, p=0.09; mean lumen diameter 1.84±0.65mm vs 1.86±0.76mm, p=0.74). Conclusions: During the first year post CABG SVGs undergo significant negative remodeling, inferred by lumen constriction, which is not observed in LIMA grafts and the grafted native coronary arteries. The impact of this negative remodeling on clinical outcomes remains to be determined.