tbuckley/cabot-search huggingface dataset:
Abstract 18610: Left Atrial Thrombus Formation After the Left Atrial Appendage Exclusion With a Novel Endoepicardial Suture Device (LARIAT®)
Authors: Ajay Vallakati, Madhu Y Reddy, Doug Gibson, Matthew Price, Ted Feldman, Bradley Knight, Jie Cheng, Randall Lee, Matthew Earnest, Jayant Nath, Ryan Ferrell, Donita Atkins, Sudharani Bommana, Pranav Loyolka, Dhanunjaya Lakkireddy
Journal: Circulation (2013)

Introduction: There is no data reported on the occurrence of left atrial (LA) thrombus after LA appendage (LAA) closure with Lariat suture ligation device. We intend to identify the incidence and describe the clinical course of LA thrombi after Lariat procedure. Methods: We performed a multicenter observational study including all patients who underwent Lariat LAA exclusion. Patients underwent routine post-procedural TEE at approximately 1, 3 and 12 months follow-up. Additional TEEs were obtained as deemed necessary clinically. All patients in whom a LA thrombus was detected on TEE images were included in the study. Demographic characteristics, procedural variables, time of detection of LA thrombus were noted. Clinical course including duration of anticoagulation, serial TEEs and complications during follow up were recorded and analyzed. Results: Of the 1056 patients who underwent Lariat procedure, 8 patients (6 males; 2 females) were found to have a LA thrombus (0.007%). Median age, median CHADS2 score, median CHADS-Vasc score and median HASBLED score were 76 years, 3.5, 4.5 and 3 respectively. LA thrombus was detected after median interval of 36 days (IQR 32.5 -262.5). Thrombus was seen in close proximity of the LAA remnant in all patients. It was identified on the first follow-up TEE in all but one. In 1 patient 1.5 cm LA thrombus was seen at 427 days with prior TEEs being clear. Mean diameter of LA thrombus was 1.14 cm ± 0.3. Dabigatran was initiated in 2 patients and warfarin in the rest. After a median duration of 190 days (IQR 86-367.5), resolution of LA thrombus was observed in 7/8 patients. In 1 patient (on warfarin), there was a significant reduction in the size of the thrombus in the first and only TEE obtained 60 days after detection. In 1 patient on dabigatran, delayed resolution of thrombus was seen (occurring at 228days after detection). No embolic events were seen in any of the patients. Conclusion: Incidence of LA thrombus is rare after LARIAT LAA exclusion and can be safely managed with oral anticoagulation without any active intervention.
Abstract 18589: Safety and Tolerability of CSL112 in Subjects With Stable Atherothrombotic Disease: Results From a Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study
Authors: Pierluigi Tricoci, Denise M D’Andrea, Paul Gurbel, Marina Cuchel, Brion Winston, Robert Schott, Robert Weiss, Michael Blazing, David Corteville, Alison Bailey, Dominick J Angiolillo, Penelope Dalitz, Shelley Myles-Di Mauro, Charles Shear, John H Alexander
Journal: Circulation (2013)

Purpose: CSL112 is a novel formulation of apoA-I purified from human plasma and reconstituted to form HDL particles. Based on the ability of infused apoA-I to rapidly remove cholesterol from atherosclerotic plaque, CSL112 is being developed to reduce CV events following ACS. This phase 2a trial assessed the safety profile and pharmacokinetics (PK)/pharmacodynamics (PD) of CSL112 after a single IV infusion and is the first study of CSL112 in pts with stable atherothrombotic disease. Methods: 45 subjects were randomized to either CSL112 (1.7, 3.4, 6.8 g) or matching placebo in a 3:1 ratio. The primary safety profile was assessed by the frequency of elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (&gt;3x ULN) and study-drug-related adverse events (AEs). PK/PD assessments included apoA-I plasma concentration and serum cholesterol efflux capacity. Results: Of the 45 subjects randomized, 33 received CSL112 and 11 received placebo; 1 patient (6.8 g group) did not receive study drug and was excluded from the safety analyses. Elevations (&gt;3x ULN) in AST or ALT were not observed in any treatment group. AEs occurring within 72 h of infusion or considered drug-related by investigators were nonserious and mild except for one case of atrial fibrillation in the placebo group. AEs were reported in 5 of 7 (71.4%), 5 of 12 (41.7%), and 6 of 14 (42.9%) subjects in the CSL112 1.7, 3.4, and 6.8 g groups, respectively, compared with 3 of 11 (27.3%) subjects in the placebo group. The numeric imbalance in AEs for CSL112 groups was attributable to vessel puncture site/infusion site bruising and headache. Evaluations of mean levels and absolute change of serum creatinine over time were similar across CSL112 and placebo groups. Robust and immediate dose-related increases in baseline-corrected apoA-I AUC and Cmax were observed, resulting in similar dose-related increases in baseline-corrected total cholesterol efflux capacity. Conclusion: CSL112 was well tolerated and did not adversely impact hepatic or renal function in subjects with stable atherothrombotic disease. CSL112 represents a novel investigational approach to raise apoA-I levels and to reduce cholesterol content in atherosclerotic plaque. Additional clinical studies of CSL112 are warranted.
Abstract 18691: Stimulation of Glucagon-Like-Peptide-1 Receptor Through Exendin-4 Preserves Myocardial Performance and Prevents Cardiac Remodeling in Infarcted Myocardium
Authors: Megan DeNicola, Ting C Zhao
Journal: Circulation (2013)

Background: We have demonstrated that perfusion of GLP-1 improved myocardial functional recovery in acute myocardial ischemic injury. However, it remains unknown whether stimulation of GLP-1 receptor with exendin-4, a selective GLP-1R agonist, could initiate a protective effect in the heart. Objective: We sought to examine whether stimulation of GLP-1R would produce cardioprotection in post chronic myocardial infarction. Methods: Mouse myocardial infarction (MI) was created by ligation of the left descending artery. After 48 hrs, animals were divided into following groups: 1) MI (n=5): animals that underwent MI and received a daily of intraperitoneal injection (i.p.) saline injection as control; 2) MI + exendin-4 (n=5); infarcted mice received injection of exendin-4 (0.1mg/kg). Two weeks later, ventricular function was measured and cardiac hypertrophy were analyzed. Results: As compared to control MI hearts, in vivo stimulation of GLP-1R increased the restoration of myocardial functional recovery following MI, which was associated with the prevention of myocardial hypertrophy. GLP-1R stimulation improved the coronary effluent in post-MI hearts. Furthermore, using the in vitro established H9c2 cardiomyoblasts exposed to reactive oxidant species stimulus, we preconditioned H9c2 cardiomyoblasts with exendin-4 at a dose of 100 nmol/L for 1 hr, and they were then subjected to 2 hr of superoxide exposure. In vitro experiments show that the treatment of H9c2 with exendin-4 dramatically decreased the leakage of lactate dehydrogenase (LDH) and increased cell survival, which was also associated with the reduction of apoptosis. Conclusion: Our results indicate that GLP-1R serves as a novel approach to eliciting cardioprotection in infarcted hearts and preventing myocardial remodeling.
Abstract 12762: Cardiac Hypertrophy is Associated With Discordant Protein Turnover in Metabolic Pathways
Authors: Edward Lau, Quan Cao, Dominic Ng, Ding Wang, Maggie P Lam, Peipei Ping
Journal: Circulation (2015)

Introduction: Cardiac hypertrophy preceding heart failure is commonly associated with disrupted protein homeostasis. How alterations in protein temporal stability and turnover may contribute to disease phenotypes is poorly understood, due in part to difficulties in measuring protein half-life in the heart in vivo. Hypothesis: We hypothesize that disrupted proteostasis contributes to cardiac remodelling in part by altering the turnover rates of enzymes necessary to maintain cardiac functions. Method: We developed a technology platform combining stable isotope mass spectrometry, computational modelling and a systems genetics model to investigate the dynamics of proteome remodelling in cardiac hypertrophy over six inbred mouse strains. The mice (C57BL/6J, DBA/2J, CE/J, A/J, FVB/NJ, BALB/cJ) were selected from a panel of &gt;100 strains for their contrasting responses to isoproterenol, which permits regression modelling of proteome dynamics over phenotypic responses. Results: We completed 1,404 LC-MS/MS experiments to quantify the turnover and abundance of 3,227 proteins from 127,648 data series. We performed weighted correlation network analysis to classify the protein data into 15 modules in an unsupervised manner. Strikingly, we found that protein interaction partners and functionally related proteins share synchronous turnover, and that coordinated turnover networks overlapped with metabolic pathways. Regression models show the turnover rate of glycolytic enzymes is a positive predictor of the severity of cardiac hypertrophy in the mouse strains (r: 0.58 - 0.80), whereas the turnover of fatty acid oxidation proteins (e.g., ACAT1, ACAD10, HADHA/B, DBT, ACAA2) is negatively correlated (r: -0.66 - -0.89). Conclusion: Our study provides the first clues on the association between cardiac remodelling and protein turnover networks, and uncovered potential disease drivers that evade steady-state gene expression analysis.
Abstract 18552: Six Months of a Low-Carbohydrate versus Low-Fat Weight Loss Diet Plus Exercise: Effects on Resting and Postprandial Endothelial Function
Authors: Kerry J Stewart, Devon A Dobrosielski, Harry A Silber, Edward P Shapiro, Nae-Yuh Wang, Pamela Ouyang
Journal: Circulation (2013)

Background: A worry about low-carbohydrate (CHO) diets is that higher fat meals may adversely affect vascular function acutely, and the regular eating of such meals may lead to chronic vascular impairment. We hypothesized that the effects of a low-CHO vs. low-fat weight loss diet, each combined with exercise training for 6-months, would have similar effects on resting and postprandial endothelial function. Methods: Persons (n=77), BMI 25-42 kg/m2, 30-65 years, were randomly assigned to a low-CHO or low-fat diet, plus exercise. At 0 and 6 months, reactive hyperemia was induced after 5 minutes of upper arm occlusion of SBP. The reactive hyperemia peripheral arterial tonometry index (RH-PAT), a measure of endothelial function, was obtained at rest and 4 hours after eating a McDonald’s breakfast (900 calories, 50 fat grams). We also measured body weight, BMI, and total body fat and trunk fat % by dual-energy X-ray absorptiometry. Results: Sixty subjects (low-CHO group: n=31, 74% female; low-fat group, n=29, 72% female) completed the study. At 0 months, there were no group differences in the following and the combined values are: age, 50.0±8.7 years; weight, 215.4±32.7 lbs; BMI, 34.2±3.8 kg/m2; total body fat, 43.3±7.2%; trunk fat, 46.4±5.7%; RH-PAT, 2.32±0.44%. At 0 months, RH-PAT did not change in response to the meal in either group, overall -0.05±0.64, p=.58. At 6 months, low-CHO vs. low-fat subjects had a greater reduction in weight, -28.9±11.0 vs. -18.7± 2.0 lbs., p&lt;.01; BMI, -4.7±2.0 vs. -2.9±1.7, p&lt;.01; body fat, -6.8±4.5 vs. -4.0±3.9%, p&lt;.02. The groups did not differ in loss of trunk fat, with an overall drop of - 5.5±5.7%, p&lt;.01. At 6 months, there was no change in resting RH-PAT in either group vs. 0 months, overall +0.03±0.53, p=.64 and no group difference in resting vs. postprandial RH-PAT, overall -0.08±0.69, p=.34. Though the 6-month mean resting RH-PAT did not improve, each absolute 1% drop in trunk fat % was associated with an absolute 0.29% (relative 12.5%) increase in RH-PAT, p=.05. Body composition changes did influence postprandial RH-PAT. Conclusions: We found no adverse effects of 6-months of a low-CHO diet on resting or postprandial endothelial function. Central fat loss was associated with improved vascular function, regardless of diet.
Abstract 12780: Collagen Derived Matricryptin Robustly Promotes Angiogenesis Post-myocardial Infarction Reducing Cardiac Dysfunction
Authors: Madeleine Neuhaus, Patti R Shaver, Robert M Lust, Lisandra E de Castro Brás
Journal: Circulation (2015)

Proteolytically released extracellular matrix (ECM) fragments - matricryptins - exert biological activities usually different from those of the full-length protein and play important roles in tissue healing and regeneration. Following myocardial infarction (MI), the native ECM is cleaved by proteases during remodeling of the left ventricle (LV) originating ECM-derived peptides. Previously, we identified a collagen matricryptin, p1158/59, that is naturally generated post-MI. This study aimed to identify the biological roles of this matricryptin. We isolated cardiac fibroblasts from mouse hearts and treated cells with 1 μM of p1158/59. HUVEC cells were used to assess p1158/59 effects in angiogenesis. A permanent occlusion model of MI was used to investigate the roles of p1158/59 in post-MI remodeling. Animals were treated with p1158/59 (950 μg/day/kg body weight) or saline for 7 days post-MI. In vitro, p1158/59 increased migration of cardiac fibroblasts and robustly induced formation of a network of 3-D capillary-like tubular structures in endothelial cells (~4-fold versus negative control, p&lt;0.05). In vivo, mice treated with p1158/59 for 7 days post-MI showed enhanced expression of components of the basal membrane known to stimulate angiogenesis - Col4a1, Col4a2, and Lama1 (p&lt;0.05 for all). By immunoblotting and immunohistochemistry we observed increased vessel numbers in both the remote and infarct regions of p1158/59 treated animals compared to those treated with saline (p&lt;0.05). Increased angiogenesis in both remote and infarct regions may offer the necessary cardioprotection to mitigate the detrimental effects of hypoxia and resulting LV dysfunction post-MI. We used echocardiography to assess physiological effects. Animals treated with p1158/59 displayed preserved LV wall thickness, geometry, and contractility, resulting in reduced systolic dysfunction post-MI. Taken together, our data show that p1158/59 is a biologically active molecule with potent pro-angiogenic properties and strongly promote this matricryptin as a molecule of interest for treatment of adverse LV remodeling.
Abstract 18622: Impact of Chronic Kidney Disease and Anemia on 5-Year Mortality After Acute Myocardial Infarction
Authors: Kazuoki Dai, Ichiro Inoue, Takuji Kawagoe, Yuji Shimatani, Fumiharu Miura, Kenji Nishioka, Yasuharu Nakama, Toshiharu Oka, Kuniomi Ooi, Ayako Harima, Haruki Hashimoto, Keiko Shimamoto, Hitoshi Susawa, Syogo Matsui, Yuuichi Morita, Masaharu Ishihara
Journal: Circulation (2013)

Background: Several studies have shown that both chronic kidney disease (CKD) and anemia are risk factors for mortality in patients with acute myocardial infarction (AMI). Method: This study was undertaken to investigate prognostic utility of combination of CKD and anemia in AMI. Between January 1996 and December 2005, 878 patients with AMI underwent coronary angiography within 24 hours after the onset of chest pain. Creatinine and hemoglobin were measured on admission in these patients. CKD was defined estimated glomerular filtration rate (eGFR) of less than 60.0 ml/minute/1.73 m2 of body-surface area (stage 3-5). Anemia was defined using World Health Organization criteria (hemoglobin level &lt;13 g/dL for men and &lt;12 g/dL for women). Results: Both CKD (81% v.s. 94%, p&lt;0.0001) and anemia (82% v.s. 90%, p=0.006) were associated with lower 5-year survival rate. In patients without CKD, anemia was associated with lower 5-year survival rate (90% v.s. 95%, p=0.03) (Figure 1), but not in patients with CKD (79% v.s. 83%, p=0.46). Multivariate analysis showed that hemoglobin level on admission was an independent predictor for 5-year survival in patients without CKD (OR 1.34, 95%CI 1.06-1.70, p=0.02), but not in patients with CKD (OR 0.92, 95%CI 0.76-1.12, p=0.40). Conclusion: In patients without CKD, admission hemoglobin level was an independent predictor for death after AMI. However, in patients with CKD, prognosis after AMI was poor regardless of presence of anemia.
Abstract 12925: The Neuro-Mechanical Unloading for Acute Myocardial Infarction Strikingly Reduces the Infarct Size and Prevents Heart Failure in the Long Term <i>(Best of Basic Science Abstract)</i>
Authors: Keita Saku, Takahiro Arimura, Takamori Kakino, Takeshi Tohyama, Takuya Nishikawa, Takuya Akashi, Yoshinori Murayama, Takafumi Sakamoto, Takuya Kishi, Tomomi Ide, Kenji Sunagawa
Journal: Circulation (2015)

Introduction: Although widespread practice of early coronary intervention has reduced the acute phase mortality in myocardial infarct (MI), the late development of heart failure remains increasing at an alarming rate. Left ventricular (LV) assist device (VAD) unloads the heart, thereby decreases oxygen consumption. Vagal nerve stimulation (VNS) exerts a powerful anti-infarct effects. Hypothesis: We hypothesized that the combination of short term VAD (mechanical unloading) and VNS (neural unloading) for the ischemia/reperfusion (IR) model would prevent the late development of heart failure. Methods: In 24 dogs, we occluded the left anterior descending coronary artery for 180min and then reperfused. We unloaded LV with transvascular VAD (Impella®). We administrated transvascular VNS with a pacing catheter in the superior vena cava (10Hz). The neuro-mechanical unloading started at 90min after the onset of ischemia and ended at 60min after reperfusion. We allocated dogs into 4 groups, IR (n=7), VAD (n=6), VNS (n=4) and VAD+VNS (n=5) and compared the infarct size and cardiac function one month after IR. Results: LVAD+VNS normalized LV end-systolic elastance (IR: 6.1±3.3, VAD: 8.1±1.3, VNS: 10.6±4.5, VAD+VNS: 14.9±2.8 mmHg/ml, p&lt;0.05) and maximally lowered LV end-diastolic pressure (EDP) (16.8±6.4, 6.4±1.5, 5.3±3.1, 3.7±0.4 mmHg, p&lt;0.05). NT-proBNP paralleled the changes in LVEDP (3712±1141, 1728±348, 1507±511, 1059±397 mmHg, p&lt;0.05), supporting nearly normalized cardiac function. VAD+VNS strikingly reduced the infarct size by more than 70% (p&lt;0.05, Figure). Conclusions: The combination of short term VAD and VNS prior to reperfusion markedly reduces the infarct size and prevents the late development of heart failure. The fact that we can deliver both VAD and VNS transvascularly indicates that the neuro-mechanical unloading therapy is clinically applicable and would improve the long term survival in post-MI patients with coronary intervention.
Abstract 13122: Hax1 Mediates Hippo Pathway to Enhance Therapeutic Effect of Sca1 <sup>+</sup> Cardiac Stem Cell Against Myocardial Ischemia
Authors: Wenfeng Cai, Lei Wang, Wei Huang, Christian Paul, Meifeng Xu, Ronald W Millard, Yigang Wang
Journal: Circulation (2015)

Background: The Hippo pathway can regulate the fate and metabolic function of stem/progenitor cells through a kinase cascade that impinges on the transcription of growth-regulatory genes. This study investigates the role of HCLS-associated protein X-1 (HAX1) on the Hippo pathway with a goal of enhancing the therapeutic effects of sca1 + cardiac stem cells (CSCs sca1+ ) in mouse ischemic hearts. Methods and Results: Western Blot assessment showed that phosphorylation levels of Yes-associated protein (Yap), the terminal effector of Hippo pathway, was increased in CSCs sca1+ when endogenous HAX1 gene expression was silenced, whereas lentiviral over-expression of HAX1 maintained Yap activation by inhibiting its phosphorylation at Serine-397. ImageStream flow cytometry was then used to observe the enhanced nuclear translocation of Yap. Hypoxia exposure promoted this translocation to a greater extent in HAX1-overexpressing CSCs sca1+ (CSCs HAX1 ) than non-encoding DNA sequence-transduced CSCs sca1+ (CSCs Null ) ( Fig 1A ). HAX-1 over-expression enhanced cardioprotective molecular mechanisms by restraining the dissipation of mitochondrial membrane potential (Fig 1B) , inhibiting endoplasmic reticulum stress response, promoting HIF-1α expression, and upregulating anti-fibrotic gene expression in CSCs sca1+ response to hypoxia injury. Echocardiography and histological assessment demonstrated that contractile function was significantly improved and cardiac fibrosis was decreased in ischemic mouse hearts post engraftment of CSCs HAX1 when compared with those of the CSCs Null -transplanted group ( Fig 1C ). Conclusion: HAX1 over-expression can regulate Hippo signal and promote nuclear translocation of Yap, upregulating intrinsic protective mechanisms of CSCs sca1+ . This results in greater improvement of cardiac function in ischemic hearts post transplantation of HAX1 over-expressing CSCs sca1+ .
Abstract 12617: Decreased Mitral Valve Area During Exercise After Restrictive Mitral Annuloplasty in Functional Mitral Regurgitation is Associated With Absence of Left Ventricular Reverse Remodeling and Subsequent Worse Clinical Outcome
Authors: Annelieke H Petrus, Jerry Braun, Laurens F Tops, Eduard R Holman, Nina A Marsan, Michel I Versteegh, Martin J Schalij, Jeroen J Bax, Robert J Klautz
Journal: Circulation (2015)

Introduction: Restrictive mitral annuloplasty (RMA) can provide a durable solution for functional mitral regurgitation (MR). Implantation of a downsized annuloplasty ring might however induce mitral stenosis at rest or, more pronounced, during exercise, with potential clinical impact. Hypothesis: We evaluated the hypothesis that RMA does not induce a clinically relevant functional mitral stenosis during exercise. Methods: Semi-supine bicycle exercise echocardiography was performed in 32 patients after RMA (ring sizes 24 or 26) for functional MR. Left ventricular volumes and ejection fraction, transmitral gradients and mitral valve area (MVA by VTI) were assessed at rest and during peak exercise and compared with preoperative echocardiographic data. Clinical events (all-cause mortality and hospital readmission for heart failure) were prospectively collected from the study visit until May 2015. Results: Exercise echocardiography was performed 77 ± 35 months after RMA. In 25 patients MVA significantly increased during exercise (1.6 ± 0.4 to 2.0 ± 0.6 cm2, p &lt;0.001), whereas MVA decreased in 7 patients (1.8 ± 0.5 to 1.5 ± 0.4 cm2, p &lt;0.05). In patients with increased exercise MVA, LV end diastolic volumes at rest were reduced compared to preoperative echocardiographic data (190 ± 72 ml vs 144 ± 62 ml, p &lt;0.01) with improved ejection fraction (36 ± 11 vs 40 ± 10 %, p &lt;0.05). In contrast, in patients with decreased exercise MVA, LV reverse remodeling was absent (LVEDV 174 ± 54 ml preoperatively vs 189 ± 80 ml at rest; NS) and ejection fraction unchanged (37 ± 8 vs 33 ± 9 %, respectively; NS). Patients with decreased exercise MVA had worse event-free survival at 22 ± 6 months after the study visit (92 vs 57 %, p &lt;0.05). Conclusions: Hemodynamically significant mitral stenosis was not observed at rest nor during peak exercise after RMA. A decrease in MVA during exercise was related to absence of LV reverse remodeling between surgery and exercise echocardiography examination. Event-free survival was significantly worse in patients with decreased exercise MVA. In conclusion, not the insertion of a downsized mitral annuloplasty ring, but the absence of LV reverse remodeling is associated with the occurrence of decreased MVA during exercise and subsequent worse clinical outcome.