tbuckley/cabot-search huggingface dataset:
Abstract 19390: Sirtuin 1 Modulates Cardiac Sodium Channels in vivo
Authors: Shengchuan Dai, Ajay Kumar, Zahid Islam, christopher lewarchik, Asma Naqvi, Kaikobad Irani, Barry London
Journal: Circulation (2012)

The rapid upstroke in phase 0 of the cardiac action potential is the result of the inward sodium current (I Na ) carried by the cardiac voltage-gated sodium channel Na v 1.5 (SCN5A). We recently reported that the overexpression of Silent Information Regulator 1 (Sirtuin 1, SIRT1), an NAD + dependent protein deacetylase, deacetylated SCN5A, increased its cell surface expression, and increased I Na in HEK-293 cells and rat neonatal cardiac myocytes. Overexpression of a dominant negative SIRT1 construct decreased SCN5A cell surface expression and I Na . The role of acetylation of SCN5A and its regulation by SIRT1 has not been shown in vivo, however. We engineered cardiac specific Sirt1 knockout (cSirt1KO) mice by breeding Sirt1 flox/flox with α-MHC-cre mice on a C57BL-6 background. cSirt1KO compared to littermate Sirt1 flox/flox mice showed much less expression of Sirt1 mRNA (12±6%, n=3) and protein in the heart but not in the kidney, and Scn5a immunoprecipitated from cardiac membrane fractions of the cSirt1KO mice showed an ∼2-fold increase in acetylation (Figure A). At 3 months of age, EKGs from anesthetized cSirt1KO compared to littermate Sirt1 flox/flox mice showed PR prolongation (43±3 ms, n=4, vs. 37±2 ms, n=5; p&lt;0.02) and telemetry from ambulatory cSirt1KO mice showed high degree heart block not seen in the controls (Figure B). Thus, our results show that Scn5a is acetylated in vivo in the mouse, that the degree of acetylation is regulated by cardiac-specific expression of Sirt1, and that decreases in Sirt1 lead to conduction disease similar to those seen in Scn5a +/- mice. These findings raise the possibility that pharmacological manipulation of Sirt1 may provide a means to modulate cardiac I Na and arrhythmias.
Abstract 19321: Novel 3D Microengineered Heart Valve Construct Mimics Early Calcific Aortic Valve Disease
Authors: Jesper Hjortnaes, Gulden Camci-Unal, Lilian Lax, Jolanda Kluin, Frederick J Schoen, Ali Khademhosseini, Elena Aikawa
Journal: Circulation (2012)

Objective: In calcific aortic valve disease (CAVD), evidence suggests that pro-inflammatory cues stimulate valvular interstitial cells (VIC) to undergo phenotypic modulation to osteoblast-like cells, leading to the formation of calcific nodules. However, the exact mechanism is unknown. We aim to engineer a novel 3D tissue model of CAVD to study the pro-inflammatory mechanisms of CAVD. This model uses a microengineered construct of natural ECM polymers of the native valve that mimics the extracellular matrix (ECM) environment of native tissue. Methods and Results: Porcine aortic VICs were encapsulated in photocrosslinkable hydrogels comprised of hyaluronic acid and gelatin methacrylate. These cell-laden 3D constructs were cultured in control (NM) (n=3) and osteogenic media (OM) (n=3), with (n=3) and without pro-inflammatory cytokine Tumor Necrosis Factor alpha (TNFα) (10 ng/mL) for up to 21 days. VIC viability was more than 90% after 21 days in culture. In healthy valves VICs are characterized by minimally expressed α-Smooth Muscle Actin (α-SMA). Under pathological conditions, VICs differentiate into activated myofibroblasts with abundant expression of α-SMA. We showed that, when our heart valve constructs were cultured in OM, α-SMA expression gradually decreased while an increase of Runx2, a transcription factor upregulated in osteoblast-like cells, was observed. Constructs exposed to OM revealed a time-dependent induction of calcified noduli formation, where alkaline phosphatase (ALP) activity showed a peak at day 14 (d1: 0.45±0.11 vs d14: 1.96±0.11 vs d21: 0.88±0.07 U/mL (p &lt;0.05)) and calcium deposition follows ALP activity and reaches a plateau at day 16 to day 21 (d1: 0.4 μ g/mL vs. d16 11.9 μ g/mL (p&lt;00.5) vs d21: 10.6 μ g/mL (p &gt;0.05)). Stimulation of heart valve constructs grown in OM with TNFα showed an increase in the amount of calcified noduli compared to without TNFα (d21: 69±7 vs 47±4 noduli (p&lt;0.05)) and promoted Runx2 expression, suggesting a direct effect of pro-inflammatory cues on valvular calcification. Conclusions: Our novel in vitro 3D heart valve model simulates events that occur during early CAVD in vivo, in which pro-inflammatory mechanisms play an important role. This model provides a new platform to study mechanisms of CAVD.
Abstract 19616: Down-Regulation of miR-23/27/24 Clusters by TGF-β1 Signalling Induces Phenotypic Switching of Vascular Smooth Muscle Cells in <i>vitro</i> and in Response to Vascular Injury in <i>vivo</i>
Authors: Claudio Iaconetti, Alberto Polimeni, Sabato Sorrentino, Jolanda Sabatino, Clarice Gareri, Francesco Passafaro, Maria Colangelo, Caterina Covello, Filomena Caria, Alessandra Carvelli, Antonio Curcio, Salvatore De Rosa, Ciro Indolfi
Journal: Circulation (2012)

Background: The differentiated state of SMCs plays a key role in the pathogenesis of several major human diseases, including atherosclerosis and restenosis after vascular injury. Several miRNAs have recently been implicated in vascular smooth muscle cells differentiation and/or phenotypic switching. Members of the miR-23/27/24 clusters are highly expressed in smooth muscle cells and are involved in cell cycle control, proliferation and differentiation of various cell types. However, the role of miR-23/27/24 clusters in vascular disease is currently unknown. Thus, the aim of the present study was to evaluate the role of miR-23/27/24 cluster on SMC differentiation and proliferation in vitro and after vascular injury in vivo. Methods and Results: To determine the expression changes of miRNAs in vascular wall with neointimal formation in vivo , we used the standard rat carotid artery balloon injury model. Using real-time PCR, we demonstrated for the first time that expression of miR-24 and miRNAs that are clustered with it (members of the miR-23 and miR-27 families) are consistently downregulated 3 and 7 days after vascular injury. Furthermore, in vitro studies showed that TGF-β1 down-regulated miR-23/27/24 clusters expression in a dose- and time-dependent manner. By using both gain-of-function and loss-of-function approaches, we found that members of the miR-23/27/24 clusters promote multiple aspects of vascular smooth muscle cell contractile phenotype and alter TGF-β1 pathway signalling. Inhibition of miR-23a/b increased gene expression of SMAD-2 and SMAD-3, while ectopic expression of miR-24 reduces the mRNA and protein levels of different genes that regulate cell-cycle progression. Also, using BrdU incorporation and cell migration assay, we demonstrate that miR-24 inhibits vascular smooth muscle cell proliferation and migration. Furthermore, systemic delivery of miR-24 mimics markedly decreased neointimal hyperplasia after balloon injury. Conclusions: We demonstrated that miR-23/27/24 clusters control TGF-β1 pathway signalling in vascular smooth muscle cell in vitro and in vivo . These findings suggest that members of the miR-23/27/24 clusters may have the potential to suppress neointimal hyperplasia after arterial injury.
Abstract 19408: Noninvasive Electrocardiographic Imaging Demonstrates Early Structural and Functional Changes Associated with Paroxysmal Atrial Fibrillation in Humans
Authors: Arpit Agrawal, Ramya Vijayakumar, Phillip S Cuculich
Journal: Circulation (2012)

BACKGROUND: Atrial fibrillation (AF) causes and perpetuates with a remodeling process that involves both functional (ion channel, connexin) and structural (fibrosis) changes to atrial tissue. Presently, there is no noninvasive method to study this process in humans. Noninvasive electrocardiographic imaging (ECGI) could provide insight into remodeling processes associated with early AF. METHODS: Noninvasive ECGI was performed during sinus rhythm on 20 patients with a history of paroxysmal AF undergoing pulmonary vein isolation procedure after antiarrhythmic drug washout period. Eight patients with no history of AF and normal ventricular function were used for controls. For functional analysis, total atrial conduction time (TACT) and left atrial conduction time (LACT) were measured. For structural analysis, left atrial posterior wall (LAPW) voltage was measured. To account for patient-specific torso variability, this value was indexed to the maximal left atrial appendage voltage (indexed LAPW). RESULTS: Compared to controls, patients with AF had longer TACT (100 vs. 79 ms control, p&lt;0.005) and longer LACT (55 vs. 39 ms control, p = 0.034, top left figure). There were no differences in raw LAPW voltage (0.40 vs. 0.47 mV control, p = 0.53), but significant differences existed after adjusting for patient-specific torso variability (0.36 vs. 0.64 mV control, p &lt; 0.020, top right figure). These differences were strongly associated with duration of PAF diagnosis. Subtle functional differences were observed early in AF, while significant functional and structural changes were seen with AF diagnosis of longer duration (5+ years, see bottom figure). CONCLUSIONS: Very early in human AF, functional effects of ion channel and connexin remodeling are evident with delayed global and regional electrical activation. With longer AF, more pronounced delay and measurable decrease in electrogram voltage are likely a combined effect of ion channel adaptation and early fibrosis.
Abstract 19410: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67 <sup>phox</sup> Attenuates Constitutively Active α&amp;rtf-inf-start;1B&amp;rtf-inf-end;-Adrenergic Receptor-Induced Cardiac Hypertrophy in Transgenic Mice
Authors: Qiong Zhao, Guiqing Zhao, Chongxu Zhang, Lei Xiao
Journal: Circulation (2012)

Transgenic (Tg) mice with cardiac-specific overexpression of a constitutively active mutant (CAM) α 1B -adrenergic receptor (AR) was reported to induce cardiac hypertrophy. We had reported a Tg mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67 phox that inhibits NOX activity. To test the role of NOX in α 1B -AR induced cardiac hypertrophy in vivo , these two Tg mice were crossed to generate Tg mice with cardiac-specific overexpression of both CAM-α 1B -AR (A1B) and DN-p67 phox (DNp67) transgenes. Age (12-week), gender, and body weight-matched mice from the following 4 groups (12 mice/group, each gender): wild type (WT), A1B, A1B/DNp67 &amp; DNp67 were subjected to 2-D echocardiography (echo) to determine the following parameters: left ventricular myocardial area (LVMA), LV wall thickness at end diastole, LV ejection fraction (EF), and LV mass. The LVEF (mean 46-54%) was not statistically different among all groups. DNp67 mice showed no significant difference in LVMA, LV mass &amp; wall thickness vs. WT (Table 1). The A1B mice showed significant increase ( p &lt;0.05) in LVMA, LV mass &amp; wall thickness indicating LV hypertrophy vs. WT; whereas the A1B/DNp67 mice showed significantly ( p &lt;0.05) decreased hypertrophy vs. A1B mice but statistically no difference from the DNp67 mice. These data suggested that A1B-induced LV hypertrophy was attenuated in the A1B/DNp67 dual Tg mice. The hearts of the above mice were then harvested after echo, and their mRNA expression of fetal genes including ANF, skeletal alpha actin, β-MHC, and 4 fibrosis genes (no difference among 4 groups, n=3) was quantified using real-time RT-PCR. All the above 3 fetal genes were significantly increased in the A1B hearts vs. WT, and were all significantly (n=4, p &lt;0.05) attenuated in the A1B/DNp67 mice. In summary, our results showed that selective inhibition of myocardial NOX subunit p67 phox attenuated α 1B -AR-induced cardiac hypertrophy in Tg mice. .
Abstract 8699: Validation of Speckle Tracking Echocardiography in Assessment of Left Atrial Volume and Function: a Comparative Study with Three-dimensional Computed Tomography
Authors: Reiko Matsuoka, Ryuhei Tanaka, Takeshi Hirose, Takatomo Watanabe, Kaoru Chikamatsu, Nobuo Kako, Maki Nagaya, Noriyuki Onishi, Noriaki Sato, Tomoko Fujii, Makoto Iwama, Koji Ono, Shintaro Tanihata, Toshiyuki Noda, Sachiro Watanabe, Masanori Kawasaki, Shinya Minatoguchi
Journal: Circulation (2011)

Background: Noninvasive assessment of left atrial (LA) function was limited by a lack of a suitable method and automated LA border detection with acoustic quantification was expected to facilitate the assessment of LA volume and function. Speckle tracking echocardiography (STE) (ACUSON sequoia 512, Siemens) which can detect LA border and provide time-LA volume curve automatically has been recently used to assess LA function. Thus, the aim of this study was to validate STE in assessment of LA volume (LAV) and function compared with 3-dimensional computed tomography (CT). Methods : Maximum (max.) and minimum (min.) LAV measured using Simpson's rule in apical 4-chamber view and LA total emptying function (EF) were compared to manual tracing method in 66 subjects in a blind way and were compared to CT with 64 rows in 20 subjects undergoing catheter ablation. Interobserver variability of max. LAV and min. LAV and LA total EF by STE in 66 subjects was determined by 2 observers in a blind way. Intraobserver variability of those parameters by STE in 66 subjects was determined by one observer with 7 days interval. LA total EF was defined as (max. LAV - min. LAV) / max. LAV. Results : LAV and LA total EF were easily and quickly obtained by STE. There was a good correlation between STE and manual tracing method in max. LAV, min. LAV and LA total EF (r=0.98, r=0.98 and r=0.95, respectively, p&lt;0.001). There was also a good correlation between STE and CT in those parameters (r=0.95, r=0.96 and r=0.97, respectively, p&lt;0.001). Bland-Altman analysis between STE and CT in those parameters revealed an excellent correlation. The interobserver correlation coefficient and relative differences in max. and min. LAV and LA total EF by STE were 0.98 and 0.94±6.8%, 0.99 and 8.0±11% and 0.99 and 2.2±15.9%, respectively. The intraobserver correlation coefficient and relative differences in those were 0.98 and 2.6±6.2%, 0.98 and 8.1±11.6% and 0.90 and 4.0±12.4%, respectively. Conclusion: Max. LAV, min. LAV and LA total EF determined from time-LA volume curve by STE exhibited a good agreement with those determined by the manual and CT method. STE had an excellent feasibility as a noninvasive estimation of LA and may be no less useful in the routine clinical setting for the evaluation of LA volume and function than CT.
Abstract 8973: p21-Activated Kinase-Mineralocorticoid Receptor Pathway Aggravates Cardiac Inflammation and Remodeling in Hypertensive Rats with Large Blood Pressure Variability
Authors: Suguru Yasuoka, Hisashi Kai, Hidemi Kajimoto, Hiroshi Kudo, Narimasa Takayama, Takahiro Anegawa, Yuji Aoki, Yoshiko Iwamoto, Kenji Fukuda, Tsutomu Imaizumi
Journal: Circulation (2011)

Background: Hypertensive patients with large blood pressure variability (BPV) show aggravated end-organ damage. There is increasing evidence that aldosterone contributes to hypertensive organ damage via mineralocorticoid receptor (MR) activation. Recently, Rac-p21-activated kinase (PAK) pathway is highlighted as an activator of MRs in the renal tubular cells. The aims of this study were to investigate whether large BPV would activate MRs in the hearts in SHR and to determine whether a specific MR blocker, eplerenone, at a non-depressor dose would prevent the large BPV-induced aggravation of hypertensive cardiac remodeling. Methods and Results: SHRs (n=76) were fed with normal salt diet. A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHR. SAD increased BPV (P&lt;0.05) without changing mean BP in SHR. Large BPV induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac myocyte hypertrophy, resulting in LV systolic dysfunction (P&lt;0.05 for each). Immunohistostaining revealed the expressions of MR and PAK in the coronary medial cells and to a lesser extent the cardiac myocytes in SHR. Large BPV induced the translocation of the MRs into the nuclei (i.e. MR activation) and increased PAK phosphorylation (i.e. PAK activation) in the coronary medial cells. Chronic administration of a subdepressor dose of eplerenone prevented the MR translocation, macrophage infiltration, myocardial fibrosis, myocyte hypertrophy, and LV dysfunction (P&lt;0.05 for each), while not affecting BPV. Circulating levels of aldosterone, corticosterone, active renin, and angiotensin II were not changed by large BPV in SHR. Conclusion: Large BPV activated PAK and MR in the coronary medial cells and aggravated perivascular inflammation, cardiac remodeling, and LV dysfunction in SHR, which were prevented by eplerenone. Thus, the PAK-MR pathway activation may play a role in cardiac inflammation and remodeling induced by large BPV superimposed upon hypertension. Eplerenone may be useful for treatment of hypertensives with large BPV.
Abstract 217: Presenting Rhythm and Outcome Following In-Hospital Cardiac Arrest in the United Kingdom: Results from the National Cardiac Arrest Audit
Authors: Krishna Patel, Edel Gallagher, Jerry Nolan, Jasmeet Soar, David Harrison, Kathryn Rowan
Journal: Circulation (2012)

The National Cardiac Arrest Audit (NCAA) is a clinical audit of in-hospital cardiac arrest that aims to improve resuscitation care and outcomes in the United Kingdom (UK). NCAA is a collaboration between the Resuscitation Council (UK) and the Intensive Care National Audit &amp; Research Centre (ICNARC) and is subscription-based. Inclusion criteria are all individuals (excluding neonates) receiving chest compressions and/or defibrillation and attended by a hospital-based resuscitation team (or equivalent) in response to an emergency call. Of 136 hospitals now participating, 83 had data for the period 1 April 2011 to 31 March 2012 and were included in the analysis. These hospitals were distributed across England and Wales and 43% were teaching hospitals. A total of 8,867 in-hospital cardiac arrests were reported for 8,499 patients (range 6 to 360 across individual hospitals). Mean age was 73 years and 57% were male. Of the 7,936 (90%) arrests with a known presenting rhythm, 4,201 (53%) presented with PEA, 2,157 (27%) asystole, 1,032 (13%) VF, 470 (6%) VT and 76 (1%) with bradycardia with a pulse. Overall, return of spontaneous circulation (ROSC) for &gt; 20 minutes was achieved following 4,006 (45%) arrests and 20% survived to hospital discharge. ROSC for &gt; 20 minutes and hospital survival varied substantially by presenting rhythm and by hospital. For example, after VF arrest, overall, 48% of patients survived to hospital discharge but this varied considerably across hospitals (Figure 1). These data indicate the need for an accurate, multivariable risk model, incorporating presenting rhythm and other important risk factors, to be able to assess performance across UK hospitals.
Abstract 8570: A Randomized, Double-blind, Controlled, Comparative Trial of Formula Food Containing Soy Protein versus Milk Protein in Visceral Fat Obesity: FLAVO study
Authors: Yoshinari Uehara, Takahira Masaya, Keita Noda, Bo Zhang, Ryoko Mitsutake, Masahiro Ogawa, Tatsuyuki Kakuma, Keijiro Saku
Journal: Circulation (2011)

To clarify the efficacy of soy at reducing visceral fat, we planned a randomized, double-blind, controlled, comparative trial that compared formula food containing soy bean protein (SP) to the same food in which soy was replaced by milk protein (MP). Forty-eight participants were enrolled for the treatment of visceral fat obesity: visceral fat area greater than 100cm 2 as calculated by CT. The SP formula contained 12g of soy bean protein, 9g of milk protein, and other nutrients, and was administered for 20 weeks in the morning, while in the MP formula soy bean protein was replaced by milk protein. During the 20 weeks of the trial period, visceral fat area and subcutaneous fat area in MP group were significantly reduced, while those in SP group did not change as assessed by an analysis of covariance. While waist circumference was reduced in both SP and MP groups, BW and BMI were significantly reduced only in MP group. Based on a mixed-effects model, the difference in log-transformed visceral fat profiles between the two groups was statistically significant (p&lt;0.05), while a negative relationship was observed between the changes in visceral fat and adiponectin in the MP group (p&lt;0.001), but not in SP group. In conclusion, formula containing milk protein is superior to that containing soy bean protein for reducing visceral and subcutaneous fat.
Abstract 9205: CT Angiography-Based Coronary Risk Stratification in Subjects Presenting with No or Atypical Symptoms
Authors: Shinichiro Fujimoto, Takeshi Kondo, Takahide Kodama, Tadaaki Orihara, Junichi Sugiyama, Makoto Kondo, Akira Endo, Hiroshi Fukazawa, Hideki Nagaoka, Akitsugu Oida, Shinichi Takase, Jagat Narula
Journal: Circulation (2011)

Backgrounds: Coronary CT angiographic (CTA) findings of positive vessel remodeling (PR, index&gt;1.1) and low-attenuation plaque (LAP, &lt;30HU) referred to as 2-feature-positive plaques (2FPP) have been reported to be associated with development of subsequent acute coronary syndromes. Such angiographic observations coupled with recent technological advances in CT technology to reduce the dose of contrast medium and radiation exposure, may allow extension of indications for CTA for risk stratification in patients with asymptomatic and atypical chest symptom. Methods: 1139 subjects (M:F=602:537, ages 30-74, 61.5±9.3 yrs) either asymptomatic or presenting with atypical chest symptom underwent coronary 64 or 320-slice MDCT angiography and coronary artery calcium scoring (CACS). Age, gender, coronary risk factors, including hypertension (HT), diabetes (DM), hyperlipidemia (HL), smoking, and and CACS were investigated as predictors for 2FPP by multivariable analysis using logistic regression analysis. Results: 2FPP were observed in 72 patients (6.3%). Based on the Framingham Risk Score (FRS) assignments, 2FPP were observed in 0/94 (0.0%) in low, 35/806 (4.3%) in intermediate, and 3/239 (15.5%) in high risk group subjects. Logistic regression analysis revealed significant predictor for 2FPP to be a male (OR: 2.6, 95%CI 1.4-34.9, p=0.004), DM (2.4, 1.4-4.0, p=0.001), smoking (2, 1.1-3. 4, p=0.02), CACS 1-500 (2.3, 1.3-4.2, p=0.007) in intermediate and high risk group subjects. 2FPP were observed in CACS categories as follows:Risk Group CACS 0 CACS 1-500 CACS&gt;500Intermediate 14/430 (3.3%) 19/345 (5.5%) 2/31 (6.5%)High 4/57 (7.0%) 29/150 (19.3%) 4/32 (12.5%) Conclusions: In asymptomatic subjects and those presenting with atypical chest pain in intermediate-risk group, CTCA is contributory to FRS. In patients with high FRS risk, 2FPP prevalence in CACS&gt;500 was lower. Male gender, DM, smoking and CACS 1-500 were independent predictors of the presence of vulnerable plaques in more than intermediate-risk group.