tbuckley/cabot-search huggingface dataset:
Abstract 18184: Deficiency in the Novel Small Leucin-Rich Repeat Protein Podocan Promotes Pressure Load-Induced Cardiac Hypertrophy
Authors: Walter S Speidl, Lincoln Shenje, Juan J Badimon, David J Schneider, Paul Klotman, Randolph Hutter
Journal: Circulation (2013)

Background: Extracellular matrix (ECM) molecules have been increasingly implicated in cardiac remodeling, and in particular the myocardial response to pressure overload. Podocan is a novel member of the small leucin-rich-repeat protein family of ECM proteins. We recently have characterized podocan as an inhibitor of the migration and proliferation of vascular smooth muscle cells. Now we are testing if podocan deficiency has an effect on pressure load-induced cardiac hypertrophy. Methods and Results: We induced pressure overload cardiac hypertrophy using aortic banding (AB) in mice (age 10-12 weeks) with podocan-/- (n=6) and wild-type (WT) (n=7) genotype. Four weeks after AB, cardiac anatomy and function were assessed by echocardiography. In addition, histological analysis was used to assess the myocardial response to AB. Podocan-deficient mice showed significantly greater cardiac hypertrophy compared with WT mice after AB, whereas no significant differences were observed when comparing sham-operated animals. Heart to body weight ratio was 6±1 mg/g in WT-mice versus 10±2 mg/g with podocan-/- genotype (P&lt;0.05). The expression of podocan and non-phospho-beta catenin (NPBC), an indicator of canonical Wnt-pathway activation, were evaluated by immunohistochemistry in serial myocardial cross-sections (n=12 per animal) (data as mean % cells±SEM). Four weeks after AB, myocardium from mice with WT-genotype exhibited abundant podocan expression both extra-cellular as well as intra-cellular. Podocan expression was also seen in areas surrounding micro-vessels. As expected, podocan was absent in myocardium from podocan-/- mice. Of note, the nuclear expression of NPBC was strongly increased in podocan-/- myocardium compared with WT (34±7% vs. 11±2%, P&lt;0.05). Immunofluorescence double labeling showed colocalization of troponin-I and NPBC in hypertrophic myocardium with podocan-/- genotype. Conclusions: Deficiency in podocan promotes cardiac hypertrophy in response to pressure overload. Greater hypertrophy seen in the absence of podocan was associated with evidence of increased Wnt-pathway activation. This first report of the role of podocan in pressure overload identifies it as a novel and important regulator of myocardial remodeling.
Abstract 18765: PAR-1 Contributes to the Innate Immune Response to Viral Infection
Authors: Silvio Antoniak, Albert P Owens, Julie C Williams, Rebecca D Lee, Alice Weithäuser, Martin Baunacke, Patricia A Sheridan, Ronny Malz, Rafal Pawlinski, Burns Blaxall, Melinda A. Beck, Ursula Rauch, Nigel Mackman
Journal: Circulation (2012)

Silvio Antoniak, 2012 Finalist and Presenting Author
Abstract 9791: GPR119 Agonism Affects Lipoprotein Particle Remodeling in Dyslipidemic Monkeys
Authors: Melanie K Shadoan, Mandy L Bergquist, Janice D Wagner, Shane G Roller, Derek J Nunez, Andrew A Young, Kathleen K Brown, Judith S Prescott, Paul L Feldman
Journal: Circulation (2012)

GSK1292263 (GSK263), a small molecule agonist of G-protein coupled receptor 119 (GPR119), significantly increases fasting HDLc, and decreases triglyceride (TG), and LDLc concentrations in both diabetic and dyslipidemic patients. The mechanism of these improvements is unclear, as no other GPR119 agonists have been reported to show similar lipid effects. Studies in non-primate preclinical models have not recapitulated the breadth of lipid effects seen in patients with GSK263. Thus, the purpose of the current study was (i) to determine if dyslipidemic non-human primates respond to GSK263 and (ii) to evaluate if the lipid improvements are a GPR119 class effect by testing another potent agonist (GSK706) as a comparator. We used a 3-period crossover design with 2 weeks active treatment followed by a 2 week washout period to evaluate the effects of Vehicle, GSK263 (25 mg/kg, comparable exposure to a clinically efficacious dose), and GSK706 (10 mg/kg, to achieve bio-equivalent GPR119 agonism to GSK263) in hypertriglyceridemic cynomolgus monkeys (N=15). Drug was administered once daily in a piece of fruit which was voluntarily consumed. For each treatment period, fasting plasma lipids and lipoproteins (by FPLC and NMR, LipoProfile®) were assessed at baseline and after 14 days of dosing. Neither GSK263 nor GSK706 had significant effects on LDLc or fasting TG, but both robustly increased HDLc by ∼20%, similar in magnitude to that seen in patients. NMR analysis shows that treatment with GSK263 and GSK706 (i) decreased number of LDL particles by ∼20%, decreased number of small, dense LDL particles by ∼36%, increased LDL size by ∼1%; (ii) increased HDL size by ∼3%, increased number of large HDL particles by ∼23%, decreased number of small HDL particles by ∼32%; (iii) decreased number of large VLDL/chylomicrons by ∼30% and tended to increase the number of small VLDL particles. Two selective GPR119 agonists have been shown to shift lipoprotein particle remodeling in the direction of potential cardiovascular benefit in monkeys. The effects of GSK263 on lipoprotein metabolism in the dyslipidemic monkey are largely concordant with the human clinical results and may suggest a receptor class effect, since both GPR119 agonists confer the same lipid improvements.
Abstract 9934: Biventricular Assist Device May be Superior to Left Ventricular Assist Device for Crash and Burn Patients
Authors: Jamie Moriguchi, Pranav Kansara, Evan Kransdorf, Michelle Kittleson, Jignesh Patel, Carmelita Runyan, Charito Olay, Rhodora Jocson, Lawrence Czer, Fardad Esmailian, Jon Kobashigawa
Journal: Circulation (2012)

Purpose: Over 15,000 left ventricular assist devices (LVADs; HeartMate I and II) have been implanted world-wide as bridge to transplant or destination in the last decade and appears to be the device of choice. However, the 1 year survival and success to transplant rates are not uniform across the INTERMACS profile spectrum. Current 6 month survival for INTERMACS profile 1 patients undergoing VAD support as bridge to transplant is 60%. We reviewed our more recent experience with both biventricular assist device (BiVAD) and LVAD support to compare the effectiveness and success rates for these two bridging modalities in this critically-ill cohort of patients. Methods: Between Jan 2007 and Mar 2012, we reviewed 56 INTERMACS profile 1 patients. 32 patients who appeared to have adequate right ventricular function received the LVAD (20 HeartMate I and 12 HeartMate II) alone while the remaining 24 patients were supported with a pneumatic BiVAD. Successful bridge to transplant, recovery and ongoing support at 6 months were analyzed among these groups. Results: 21/24 BiVAD patients vs 11/32 LVAD pts (88% vs 34%, p&lt;0.001) were successfully transplanted or explanted due to recovery of cardiac function. Of the LVAD patients, 7/20 HeartMate II patients vs 4/12 HeartMate I patients (35% vs 33%, p=0.93) were successfully transplanted or explanted due to recovery of cardiac function. Multivariate analysis suggested that inotropic support more than 14 days post VAD implantation in LVAD patients was associated with increased mortality. 2/3 BiVAD deaths and 13/21 LVAD deaths were due to progressive shock, hemorrhage or right ventricular failure. 1-year survival post transplant was 18/20 (90%) in the BiVAD group and 11/11 (100%) in the LVAD group. Conclusions: In critically-ill INTERMACS profile 1 transplant candidates, BiVAD support may result in improved outcomes compared to LVAD and could be the device of choice. In these LVAD patients, perceived adequate right ventricular function may be misleading as these are very ill INTERMACS profile 1 patients where subsequent progressive shock, hemorrhage and right ventricular failure are major causes of death.
Abstract 9785: The Contribution of CaMKII and PKA to the Development of an Increased RyR-dependent SR Ca Leak in Human Cardiac Pathology
Authors: Thomas H Fischer, Jonas Herting, André Renner, Theodor Tirilomis, Stefan Neef, Jan Gummert, Schöndube A Friedrich, Gerd Hasenfuss, Lars S Maier, Samuel Sossalla
Journal: Circulation (2012)

The mechanisms of a progressive ryanodine receptor type 2 (RyR2) dysregulation in the transition from human cardiac hypertrophy (Hy) to heart failure (HF) are still unclear. Inhibition of Ca 2+ /calmodulin-dependent kinase II (CaMKII) reduces the sarcoplasmic reticulum (SR) Ca 2+- leak and improve contractility in human HF. However, the relative contribution of CaMKII and protein kinase A are still not clear. Western blot experiments from tissue samples (n=12) of patients with afterload-induced Hy and preserved ejection fraction (EF&gt;50%) revealed an increase in RyR2 expression by 82±22% ( P =0.05) compared to healthy controls (n=5). The phosphorylation status of RyR2 at S2809 and S2815 was not altered. In human end-stage HF (n=8), a pronounced hyperphosphorylation of RyR2 could be detected at the CaMKII-dependent site S2815 (by 311±72%, P &lt;0.05) whereas the PKA-dependent site S2809 lacked differential regulation. The comparison of HF patients with and without β-blocker medication (n=7 vs. 4) did not reveal any differences as to RyR2 phosphorylation status. When isolated myocytes were paced at 1 Hz and scanned for diastolic Ca 2+ sparks (confocal microscopy, Fluo 3) a higher Ca 2+ -spark frequency (by 82±26% P &lt;0.05) was detected in HF (n=93) compared to Hy (n=94). Interestingly, PKA inhibition with H89 (5 μM) only accomplished a decrease of SR Ca 2+ -leak in Hy (by 59±13%, P =0.05, n=85 vs. 115) but not in HF (n=85 vs. 74). Stimulated Ca 2+ transients (0.5 Hz, n=31 vs. 23), SR Ca 2+ content (caffeine, n=23 vs. 22) and fractional SR Ca 2+ release (n=21 vs. 15) were not changed by H89 treatment in HF (epifluorescence microscopy, Fura 2). CaMKII inhibition by AIP (1 μM), in contrast, could significantly reduce SR Ca 2+ leak in Hy (by 63±14%, P &lt;0.05, n=93 vs. 103) as well as in HF. Thus, in human Hy with preserved EF both kinases seem to functionally regulate RyR2 gating. In end-stage human HF, however, the diastolic SR Ca 2+ leak seems to be induced by CaMKII rendering an inhibition of CaMKII a promising pharmacologic toehold.
Abstract 18401: The Immunoregulatory Cytokine FGL2 is Associated With Functional Impairment in Patients With Heart Failure
Authors: Andrzej Chruscinski, Douglas Greig, Carolina Alba, Vivek Rao, Gary Levy, Heather Ross
Journal: Circulation (2013)

Introduction: Chronic heart failure is a condition that is characterized by immune activation and release of pro-inflammatory cytokines, which are associated with worsening functional class. Fibrinogen-like protein 2 (FGL2) is a novel immunoregulatory protein that is involved in innate and adaptive immune responses. A connection between plasma FGL2 levels and heart failure has not been previously reported. Objective: To determine if there is an association between plasma FGL2 levels and functional impairment in heart failure. Methods: Seventy-four heart failure patients with NYHA FC I-IV, standard medical treatment, mean age 55 ± 11 years, mean ejection fraction of 29% ± 10%, and 23% females were included. Functional impairment was assessed by determination of peak VO2. Plasma levels of FGL2 and CRP were determined using ELISA in HF patients and healthy controls. We compared peak VO2 according to tertiles of FGL2 using ANOVA (tertile 1&lt;39.7, tertile 2=39.7 to 63.2, and tertile 3&gt;63.2 ng/ml). Correlations were assessed using Pearson’s correlation. We performed a multiple linear regression analysis to investigate the association between peak VO2 and FGL2 adjusting for variables of clinical significance and/or statistical significance. Results are provided as mean ± SD. Results: The plasma levels of FGL2 were significantly higher in HF patients compared with controls (58.6 ± 41.2 versus 32.4 ± 14.7 ng/ml, respectively, p&lt;0.001). 28% of the patients had an ischemic cardiomyopathy, 34% had hypertension, and 18% had diabetes. In HF patients, the mean peak VO2 was 16.9 ± 5.0, 14.2 ± 4.9, and 12.7 ± 3.8 ml/kg/min in the 1 st , 2 nd and 3 rd tertile of FGL2, respectively (p= 0.012). FGL2 was negatively correlated with peak VO2 (r= -0.271, p=0.026) and positively correlated with CRP (r= 0.314, p=0.011). In the adjusted regression model, FGL2 was independently associated with peak VO2 (adjusted beta estimated=-0.031, test statistic=5.77, p=0.016). Conclusion: In heart failure patients, higher levels of plasma FGL2 were associated with a greater degree of functional impairment as measured by peak VO2. These results suggest that immune activation as measured by FGL2 is associated with the severity of heart failure.
Cardiac Imaging: What Can the Future Learn From the Past?
Authors: William Brody
Journal: Circulation (2012)

Tremendous strides in the understanding of the etiology of atherosclerosis have been greatly facilitated through the introduction of new methods of imaging of the vascular system. Innovations in imaging using ultrasound, single photon and positron emitting isotopes, x-rays and nuclear magnetic resonance have provided profound insights into the anatomic distribution and enabled the development of new treatment methods including bypass surgery and angioplasty. In addition, imaging tools have helped to identify the role of the various risk factors for the development of atherosclerosis. Despite the profound reduction in morbidity and mortality of heart disease over the past 50 years, significant obstacles remain to achieve further reductions due to the challenges of sudden cardiac death, restenosis following angioplasty and bypass surgery, as well as heart failure. In the cardiovascular arena, new treatment methods have in many cases followed from the introduction of new tools for imaging the distribution and extent of atherosclerotic narrowing. The challenges for the future will be to identify those technologies with the most promise for increasing the specificity and sensitivity imaging the distribution and progression of atherosclerosis. A brief review of the evolution of diagnostic imaging and its role in understanding and treating heart and vascular disease can help define a roadmap for further advances.
Abstract 18171: Post-Exercise T-Wave Alternans as a Predictor of Fatal and Non-Fatal Cardiovascular Events
Authors: Tuomas Kenttä, Juha S Perkiömäki, M J Junttila, Olli-Pekka Piira, Samuli Lepojärvi, Heikki V Huikuri
Journal: Circulation (2013)

Purpose: T-wave alternans (TWA), a measure of beat-to-beat fluctuations in the ventricular repolarization, has been proposed to reflect the vulnerability to arrhythmic death in various populations. We tested the hypothesis that the presence of TWA may also predict non-arrhythmic cardiac events, such as heart failure and vascular events. Methods: Exercise electrocardiograms of 1017 patients with angiographically documented stable coronary artery disease (CAD) were analyzed for TWA with the modified moving average (MMA) method. End-points of the study were cardiac death, hospitalization due to heart failure, acute coronary event and stroke. Results: During a two-year follow-up, 21 patients experience cardiac death, 24 patients were hospitalized due to heart failure, 104 had acute coronary event, and 54 had stroke/transient ischemic event (TIA). TWA ≥ 23.5 μV during post-exercise recovery was predictive of cardiac death (hazard ratio [HR]: 6.72, 95% confidence interval [CI]: 1.93 - 23.37, P=0.003), but it did not predict hospitalization for heart failure (HR: 1.78, 95% CI: 0.74 - 4.29, P=0.201), occurrence of acute coronary event (HR: 1.06, 95% CI: 0.71 - 1.58, P=0.783), or stroke/TIA (HR: 1.16, 95% CI: 0.66 - 2.04, P=0.597). When adjusted with age, gender, diabetes, left ventricular ejection fraction (LVEF), maximum heart rate and baseline systolic blood pressure, maximum post-exercise TWA remained predictive of cardiac death with a multivariate hazard ratio of 5.28 (95% CI: 1.49 - 18.69, P=0.010). Conclusions: Post-exercise TWA is especifically associated with an increased risk of short-term fatal cardiac events in patients with stable CAD, but it is not a strong predictor of non-fatal cardiac events
Abstract 9829: Subclinical Atherosclerosis in Asymptomatic Subjects Referred for Risk Stratification: A Comparison of Carotid Ultrasound, Coronary Artery Calcium Scoring and Coronary Computed Tomography Angiography
Authors: Benjamin D Schroeder, G. B. John Mancini, Jonathon Leipsic, Brett Heilbron, Gordon A Francis, Carolyn M Taylor
Journal: Circulation (2012)

Introduction: In subjects free of known vascular disease, current guidelines recommend lipid targets according to global risk of cardiovascular events. In select populations, imaging is recommended for refining clinical risk. The purpose of this study was to compare three imaging modalities coronary artery calcium scoring (CACS), carotid ultrasound (US) and coronary computed tomography angiography (CCTA) in a population referred for risk stratification. Hypothesis: We hypothesized that diverse definitions of early atherosclerosis utilized by differing modalities would affect perceived prevalence of subclinical atherosclerosis and consequently, assessment of risk. We sought to determine the degree of concordance among these definitions. Methods: Subjects free of known vascular disease scheduled to undergo a carotid US for clinical risk stratification were invited to undergo CCTA/CACS. Subjects on lipid lowering therapy &gt; 3 months were excluded. All images were assessed by an experienced core laboratory. Carotid intima media thickness ≥75 th percentile for age and sex, CACS &gt; 0 and detection of either carotid or coronary artery plaque were indicators of atherosclerosis. Results: Fifty patients were included. Median age was 53 years; 54% were men. Atherosclerosis was seen in 28%, 78% and 90% of subjects using CACS, CCTA and carotid US, respectively, with all subjects demonstrating one or more markers or findings on at least one method. In the 36 patients with CACS = 0, 69% and 86% had atherosclerosis on CCTA and carotid US, respectively. Maximal concordance (68%, p = 0.021) between carotid US and CCTA was seen when carotid US showed the presence/absence of any plaque with a maximal thickness of ≥ 1.5 mm. Conclusions: In this detailed analysis, all subjects identified to warrant further risk stratification had findings indicating subclinical atherosclerosis on at least one modality. Concordance between the modalities was highly variable, dependent upon the specific definition used. Carotid US and CCTA detection of plaque were more sensitive than CACS &gt; 0. Given strong evidence for low CV risk in patients with CACS = 0, the threshold of subclinical disease at which to treat using Carotid US or CCTA plaque warrants further consideration and caution.
Abstract 9767: Direct-renin-inhibitor Aliskiren Therapy Consistently Suppresses Enhanced Cardiac Sympathetic Activity and Improves Left Ventricular Remodeling in Patients with Systolic Heart Failure
Authors: Imamura Yoshihiro, Takaki Tsutsumi, Akira Yamada
Journal: Circulation (2012)

Introduction: Adding aliskiren to heart failure (HF) therapy was reported to reduce plasma brain natriuretic peptide (BNP) concentration. However, the effects of aliskiren on cardiac sympathetic nerve activity and on cardiac function have not yet been clarified. Hypothesis: We assessed the hypothesis that adding aliskiren to standard therapy would be effective to suppress cardiac sympathetic nerve function and improve cardiac function. Methods: We enrolled 38 patients with mild HF (NYHA class II). The inclusion criteria were: 1) in stable condition for at least six months; 2) receiving standard therapy including an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker and a beta-blocker; 3) have systolic dysfunction (left ventricular ejection fraction: LVEF of &lt; 45%); 4) without diabetes; and 5) without renal dysfunction (serum creatinine of &gt; 1.2 mg/dL). We randomly assigned 18 patients to receive additional aliskiren treatment of 150 mg/d (aliskiren group), while 20 patients continued standard therapy (control). All patients underwent neurohormonal measurements, echocardiography and 123I-metaiodobenzylguanidine (MIBG) imaging. In the MIBG images, the heart/mediastinum (H/M) ratio and cardiac washout rate (WR) were determined for evaluating cardiac sympathetic activity. The follow-up data were obtained three and 12 months later. Results: In the aliskiren group, plasma renin activity and BNP fell significantly. MIBG analysis showed a consistent decrease in WR and a consistent increase in H/M ratio over 12 months only in the aliskiren group (WR %: 39.6 ± 3.1 vs 32.0 ± 2.1, 32.8 ± 3.7, p = 0.013, H/M: 2.80 ± 0.16 vs 3.12 ± 0.22, 3.05 ± 0.20 p = 0.015 at each follow-up period). The LVEF improved although not significantly (p = 0.074). The LV end-diastolic volume (EDV) and end-systolic volume (ESV) improved significantly (EDV index mL/m2: 92.8±6.4 vs 79.7±5.8, 82.3±5.3, p = 0.042 and ESV index: 56.6±4.8 vs 46.4±4.5, 48.6±4.4, p = 0.021). In the control group, these data remained unchanged. Conclusions: In HF patients receiving standard therapy but still continuing to have cardiac dysfunction, the addition of aliskiren consistently suppresses cardiac sympathetic activity over 12 months and improves left ventricular remodeling.
Abstract 9778: Harmonizing Cutoff Values for Severe Aortic Valve Stenosis
Authors: Jan Minners, Christa Gohlke-Baerwolf, Edda Bahlmann, Simon Ray, John B Chambers, Eva Gerdts, Kristian Wachtell, Anne Rossebo, Ronnie Willenheimer, Kurt Boman, Kenneth Egstrup, Terje Skjaerpe, Antero Kesaniemi, Terje R Pedersen, Philippe Brudi, Christoph A Nienaber, Franz-Josef Neumann, Nikolaus Jander
Journal: Circulation (2012)

Background: Decision making in patients with aortic valve stenosis (AS) and normal left ventricular function may be complicated by inconsistencies in cutoff values for severe AS. Particularly, the constellation of severe stenosis according to aortic valve area (AVA) &lt;1cm 2 and non-severe stenosis according to mean pressure gradient (MPG) ≤40mmHg is a frequent finding which may, at least in part, be due to systematic discrepancies between cutoff values. Methods: We evaluated the effect of adjusting the cutoff value for severe AS from AVA 1.0cm 2 to 0.8cm 2 on discrepancies in classification of severity and event rates in 1525 asymptomatic patients with normal ejection fraction prospectively followed for a mean of 46 months from the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. Results: The diagnosis of a severe AS was made in 56 (4%) patients according to the MPG &gt;40mmHg criterion, in 470 (31%) based on an AVA of &lt;1.0cm 2 and in 185 (12%) with an AVA of &lt;0.8cm 2 . After dividing the population into quintiles according to AVA and MPG an aortic valve related event rate of 0.40 was observed in patients with a mean AVA of 1.0±0.1cm 2 which was similar to patients with a MPG of 27±2mmHg (0.40, p=ns). In turn, patients with a MPG of 37±5mm had an event rate of 0.65 and patients with an AVA of 0.74±0.1cm 2 had an event rate of 0.53 (figure). Cardiovascular death rates followed a similar pattern. Conclusion: Adjusting the cutoff value for severe stenosis in patients with normal left ventricular function from AVA 1.0cm 2 to 0.8cm 2 may harmonize parameters for the assessment of aortic stenosis both with respect to stenosis severity as well as clinical outcome.