tbuckley/cabot-search huggingface dataset:
Abstract 17100: CaMKII Activity Modulates Basal Sarcoplasmic Reticulum Ca <sup>2+</sup> Cycling to Drive Normal Automaticity of Sinoatrial Node Cells
Authors: Tatiana M Vinogradova, Syevda Sirenko, Yue Li, Harold Spurgeon, Edward G Lakatta
Journal: Circulation (2011)

Spontaneous beating of rabbit sinoatrial node cells (SANC) is linked to rhythmic, sarcoplasmic reticulum (SR) generated, submembrane local Ca 2+ releases (LCR) during diastolic depolarization (DD). LCRs activate inward Na + /Ca 2+ exchange current which imparts an exponential increase to the later part of DD and brings the membrane potential to threshold to fire an action potential. Although the crucial dependence of normal SANC automaticity on CaMKII signaling has previously been linked to an effect to facilitate recovery from inactivation of L-type Ca 2+ channels, there may also be direct CaMKII-dependent regulation of LCRs in SANC. Here we show that in freshly isolated rabbit SANC CaMKII inhibitor, KN-93 (0.3 μmol/L), but not its inactive analog KN-92, markedly suppresses LCRs (confocal microscopy, Ca 2+ indicator Fluo-3) reducing LCR number per each spontaneous cycle by 64% (from 1.1±0.1 to 0.4±0.1); LCR size by 32% (from 7.0±0.6 to 4.8±0.2 μm); and by markedly prolonging the LCR period (the interval between AP-induced Ca 2+ transient and subsequent LCR). Prolongation of the LCR period predicted the concomitant increase in spontaneous cycle length, indicating that CaMKII is vitally important for spontaneous SANC firing. To further delineate mechanism of CaMKII-dependent regulation of Ca 2+ cycling, avoiding interference of L-type Ca 2+ channels, we permeabilized SANC with saponin. Confocal linescan imaging of permeabilized SANC showed that KN-93, but not KN-92, decreased the LCR number by 62% (from 16.8±3.7 to 6.4±2.0 per 1sec×100μm) and LCR size by 25% (from 6.5±1.1 to 4.9±0.8 μm). The suppression of LCR parameters was associated with a ~12% reduction of the SR Ca 2+ load, assessed by a rapid application of caffeine on permeabilized SANC. The SR Ca 2+ load is controlled by phospholamban (PLB) which could be phosphorylated by CaMKII at Thr 17 site. Basal PLB phosphorylation at Thr 17 site, assessed by western blotting, is ~3 times greater in SANC than in ventricular myocytes, and KN-93, but not KN-92, markedly decreases PLB phosphorylation by ~40%. Thus, normal automaticity of SANC is regulated by basal CaMKII-dependent phosphorylation, in part, through modulation of SR Ca 2+ cycling, i.e. SR Ca 2+ load controlled by CaMKII-dependent phosphorylation of PLB.
Abstract 19241: Characteristics of No-Reflow Phenomenon in STEMI Patients Post Thrombectomy: A Multiethnic Group Analysis
Authors: Abhishek Jaiswal, Harmony J Leighton, Emmanuel Moustakakis, Andrew J Buda, Chong H Park
Journal: Circulation (2012)

Objective: There is limited data about the characteristics of the no-reflow phenomenon in STEMI patients since the introduction of routine thrombectomy. We aimed at studying the characteristics of the no-reflow in multiethnic STEMI patients who underwent primary PCI with thrombectomy. Methods: All patients underwent primary PCI within 6 hours of their presentation. Pre-discharge LVEF was assessed by TTE (3+/-2 days post- MI). Results were then compared between patients who achieved TIMI II and III flow post PCI and the no-reflow group (TIMI 0 and I flow). Results: The 313 patients consisted of (57.2%)Caucasians,(18.5%) Asians,(12.1%) Hispanics,(8.6%) South Asians, and (3.5%)Blacks. No-reflow was seen in 14%(43/313) of patients. Gender distribution (males: 84% vs 79%) and mean age (62.8+/-5.9 yrs vs 61.7+/-6.8 yrs) were similar between the groups. Distribution of traditional risk factors: smoking (44% vs 56%), HTN (72% vs 75%), dyslipidemia (58% vs 71%), DM (30% vs 36%) and incidence of prior CAD (26% vs 25%) were similar in both groups. There were no differences in the distribution of infarct related arteries (prox. and mid LAD-58% vs 48%, RCA-28% vs 37%, LCx-5% vs 9%) in both groups. The no-reflow group had significantly higher serum CPK level on presentation (2154.8 ng/dl vs. 1465.8 ng/dl, p&lt;0.04) and lower LVEF post PCI (44.5% vs 50.3%, p&lt;0.003). However, patients with no-reflow did not have a higher incidence of cardiogenic shock (7% vs 9%), VT/V-fib (2% vs 5%), or IABP requirement (23% vs 21%). Of the ethnic groups, South Asians had significantly higher incidence (16% vs 9%, p&lt;0.05) of no-reflow. In addition, they also presented later (469 minutes vs 179 minutes, p&lt;0.007) and frequently presented with epigastric burning. Conclusions: These data support the hypothesis that the no-reflow phenomenon occurs in a significant proportion of STEMI patients despite primary PCI with thrombectomy. No-reflow resulted in a large infarct size as measured by serum CPK and less early LVEF recovery. However, no-reflow did not result in higher complications during hospitalization. Although no reflow was seen in all ethnic groups, South Asians have a higher incidence of no-reflow phenomenon. This may be attributed to their late presentation and atypical presenting symptoms.
Abstract 83: Sudden ETCO <sub>2</sub> Trend Change Alerts During Out-of-Hospital Cardiopulmonary Resuscitation Using an Automated Capnogram Analysis Algorithm
Authors: Mohamud Daya, Eric Helfenbein, Ahamed Idris, Dana Edelson, Reza Firoozabadi, Saeed Babaeizadeh, Sophia Zhou
Journal: Circulation (2011)

Background Capnography has recently become the standard-of-care for EMS personnel during out-of-hospital resuscitation to confirm tracheal tube (TT) placement and monitor quality of CPR. Although the instantaneous end-tidal CO2 (EtCO2) value is of importance, additional information can also be obtained from the EtCO2 trend. Current defibrillator/monitors do not provide alerts based on EtCO2 trends. Objective To develop a defibrillator-based capnogram analysis program to provide sudden EtCO2 trend change alerts that can be used to alert rescuers to a variety of conditions. Methods Capnogram recordings from 154 OHCA patients were collected between 2008 &amp; 2010 from two EMS agencies based in Oregon &amp; Texas. De-identified clinical charts containing EMS self-reports were also obtained which contained time histories of events. The capnogram trend algorithm contains both rising and falling detectors and uses the difference between 30-second averages of EtCO2 from two adjacent sliding windows. The rising detector uses a threshold of a 50% increase and the falling detector uses a 30% decrease threshold to trigger. Results Sudden change alerts (N = 533) generated by the algorithm were correlated with events in the EMS charts or determined by examination of EtCO2, ECG, and compression waveforms. Sudden EtCO2 falling events were associated with poorer quality or stopped chest compression, hyperventilation, TT tube misplaced or dislodged, and loss of organized rhythm. Sudden EtCO2 rise events were associated with resumed or improved chest compression, successful airway placement, improved ventilation following hyperventilation, probable ROSC, and external pacing (n = 1). The remaining sudden change alerts were associated with artifacts in the capnogram waveform or could not be correlated. Conclusion An automated capnogram analysis program can accurately detect sudden trend changes in EtCO2 and help EMS personnel identify important events during OHCA resuscitation.
Abstract 19101: Increased Sympathetic Nervous System Activity in Refractory Hypertensive Patients in Contrast to Controlled and True Resistant Hypertensive Patients
Authors: Tanja Dudenbostel, Maria C Acelajado, Suzanne Oparil, David A Calhoun
Journal: Circulation (2012)

Within the population of patients with resistant hypertension (RHTN), a unique phenotype with unexplained mechanisms of treatment failure has been identified. This phenotype remains uncontrolled despite optimal medical therapy who we refer to as having refractory hypertension (RefHTN) in contrast to true or controlled RHTN. The current study prospectively compared biochemical parameters, indices of arterial compliance, endothelial function and cardiohemodynamics in patients with RefHTN and a matched cohort of controlled and true resistant hypertensive patients. From 2009 to 2012, refractory patients were identified in a referral hypertension clinic using the following criteria: uncontrolled blood pressure (BP) on 5 or more antihypertensive medications (including chlorthalidone and spironolactone) after ≥ 3 visits within a minimum 6-month follow-up period. All 40 patients underwent measurement of 24-hr BP, heart rate (HR); pulse wave analysis (PWA); augmentation index (AIx75); aortic pulse pressure (APP); pulse wave velocity (PWV); arterial flow-mediated dilation (FMD), electrocardiogram, and impedance cardiogram. Baseline characteristics were similar; although, refractory patients were younger and were treated with an average of 7 different antihypertensive classes. ABPM confirmed a difference in systolic (177±29 vs 133±6 mm Hg, p&lt;0.001) and diastolic BP (101±17 vs 79±10 mm Hg, p&lt; 0.001) in the true or controlled vs refractory groups. Average 24-hr HR was higher in patients with RefHTN (78±8 vs 69±7 bpm, p=0.039) despite being on more β-blockers. PWV was greater(12±3 vs 10±3 m/s, p=0.044), as was AIx75 (31±7 vs 17±12 %). Brachial artery FMD was more reduced in patients with RefHTN (6.6 vs 9.4%). Impedance electrocardiogram showed significantly increased systemic vascular resistance(supine 3876.4 vs 1372.9 , p&lt;0.001 and standing 1980.1 vs 1197.7 dyne sec cm-5,p=0.037). Patients with RefHTN have increased arterial stiffness, central blood pressure,systemic vascular resistance, and endothelial dysfunction compared to patients with controlled and true RHTN, consistent with higher sympathetic activity in his group suggesting that increased adrenergic output contributes importantly to antihypertensive treatment failure.
Abstract 16812: Bone Morphogenetic Protein Signaling is Required for Vascular Calcification in a Murine Model of Matrix GLA Protein Deficiency
Authors: Rajeev Malhotra, Matthias Derwall, Ester Spagnolli, Yuko Beppu, Hannah R Shakartzi, Emmanuel S Buys, Paul B Yu, Kenneth D Bloch
Journal: Circulation (2011)

Introduction: Matrix GLA protein (MGP) is a mineral-binding extracellular matrix protein that is thought to prevent vessel calcification by sequestration of calcium ions. However, MGP also inhibits bone morphogenetic protein (BMP) signaling. MGP -/- mice exhibit severe medial arterial calcification by 2 wks and die by 6 wks from aortic aneurysm and rupture. We hypothesized that MGP prevents vascular calcification via its effects on BMP signaling. Methods: MGP -/- mice were treated with either vehicle or the small molecule BMP type I receptor inhibitor LDN-193189 (LDN, 2.5 mg/kg once daily IP) from day 1 to 28. Whole aortas were harvested for phospho-Smad 1/5/8 (P-Smad) immunohistochemistry, a marker of BMP signaling, and for Alizarin Red staining of calcium. Osteogenic activity in aortas was visualized ex vivo by the uptake of a fluorescent bisphosphonate imaging probe. MGP -/- mice were also treated with vehicle or LDN to ascertain if inhibition of BMP signaling could impact survival, using Kaplan-Meier and Cox regression analysis. Results: MGP -/- aortas demonstrated increased P-Smad compared to wild-type mice. LDN treatment of MGP -/- mice reduced aortic P-Smad levels and was associated with a reduction in tissue calcium levels (Fig. A &amp; B). Pharmacologic inhibition of BMP signaling in MGP -/- mice resulted in an 81% reduction in aortic osteogenic activity compared to vehicle-treated controls (Fig. C; n=6 in each group; normalized average intensity ± SEM, 0.19 ± 0.05 vs 1.0 ± 0.10, P&lt;0.0001), with similar reductions observed at the aortic arch and the abdominal aorta. LDN treated mice exhibited improved survival compared to vehicle-treated controls (n=10 in each group; Cox hazard ratio 0.04, 95% CI 0.01-0.17, P&lt;0.001). Conclusions: MGP prevents vascular calcification primarily via its impact on BMP signaling. Pharmacologic BMP inhibition improves survival in MGP -/- mice and may represent an important therapeutic target in the treatment of human vascular disease.
Abstract 18635: G Protein-Coupled Receptor Kinase 2 Regulates Cellular Oxidative Stress and Survival
Authors: Tiju Theccanat, Nicolas Ludmer, Shahab A Akhter
Journal: Circulation (2012)

Cardiac myocyte oxidative stress and apoptosis are considered important mechanisms for the development of heart failure (HF). Chronic HF is characterized by increased levels of circulating catecholamines to augment cardiac output. Long-term stimulation of myocardial β-adrenergic receptors (β-ARs) is known to be deleterious in cardiac myocytes, however, the potential mechanisms underlying increased cell death are unclear. We hypothesize that G protein-coupled receptor kinase-2 (GRK2), a critical regulator of myocardial β-AR signaling and function, plays an important role in mediating cellular oxidative stress and apoptotic cell death in response to β-agonist stimulation. Stimulation of H9c2 cells with a non-selective β-agonist, isoproterenol (ISO) [10 -5 M] led to a 3-fold increase in oxidative stress/reactive oxygen species (ROS) generation as quantified by Mitosox staining and a significant increase in apoptosis measured by TUNEL and caspase-3 activity compared to PBS-treated controls. There was also a 2.5-fold increase in NADPH oxidase-4 (Nox4) expression but no change in Nox2, the primary NADPH isoforms and major sources of ROS generation in cardiac myocytes. ISO stimulation led to a 3-fold increase in GRK2 activity, similar to the myocardial GRK2 activity present in chronic HF. A 3-fold adenoviral-mediated overexpression of GRK2 led to similar increases in ROS production and apoptosis as seen with ISO stimulation. The increases in oxidative stress by either ISO stimulation or GRK2 overexpression were abolished by pre-treatment with apocynin, a non-specific Nox inhibitor, or siRNA-mediated knockdown of Nox4. Direct activation of adenylyl cyclase with forskolin did not lead to increased ROS production suggesting that β-agonist-induced oxidative stress is likely mediated by activation of GRK2 and increased Nox4 activity and not cAMP/PKA. Adenoviral-mediated expression of the GRK2 inhibitor, βARKct, inhibited Nox4 upregulation, ROS production and apoptosis in response to ISO stimulation. These data demonstrate that GRK2 may play an important role in regulating oxidative stress and apoptosis in the heart and provides another mechanism for the beneficial effects of cardiac-targeted GRK2 inhibition.
Abstract 19068: Connective Tissue Growth Factor in Human Diastolic Heart Failure from the Taiwan Diastolic Heart Failure Registry and a Canine Model of Diastolic Dysfunction
Authors: Cho-Kai Wu
Journal: Circulation (2012)

BACKGROUND: Diastolic heart failure (DHF) is characterized by myocardial interstitial fibrosis and left ventricular hypertrophy. The study investigated the association between connective tissue growth factor (CTGF) and DHF from animal model to clinical indices. METHODS: The participants of current study were enrolled from the Taiwan Diastolic Heart Failure Registry (TDHFR). 1284 patients were screened and a total of 125 patients with a diagnosis of DHF confirmed by echocardiography were recruited. The severity of DHF was decided according to tissue doppler imaging (E/e’). Soluble plasma levels of CTGF were measured in all subjects and the associations with diastolic function parameters were calculated. Canine model of DHF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading (at baseline and after 2 weeks). Myocardium tissues were collected, and western blotting was used to detect the protein expression of CTGF for each dog. The correlation between CTGF, the severity of diastolic dysfunction and hemodynamic changes was then calculated. RESULTS: Patients with severe DHF presented significantly higher plasma CTGF levels than the controls. Significant correlation were found for plasma CTGF and E/e’ (r = 0.80, p&lt;0.001) in advanced DHF patients (E/e’ &gt;15). After 2 weeks in canine models, the protein expression of CTGF from LV myocardial tissue was significantly increased (p&lt;0.01) compared with the controls (shame dogs). Moreover, the expression of CTGF paralleled the severity of LV diastolic dysfunction parameters (r= 0.70, p= 0.03 for E/e’) and hemodynamic changes (r= 0.75, p= 0.02). After adjusting the possible confounding factors for diastolic dysfunction, CTGF levels were associated with diastolic parameters both in human and canine models (Plasma CTGF, B=0.064, p&lt;0.001; tissue CTGF, B= 9.87, p = 0.05). CONCLUSIONS: Both Plasma and myocardium CTGF levels had significant correlations to the severity of DHF. Our study offered the evidence to apply novel therapies for DHF patients aim to down-regulate the overexpression of CTGF.
Abstract 18689: Building a High-throughput Assay for Arrhythmogenic Cardiomyopathy Modifier Pathways in the Zebrafish
Authors: Eva Plovie Buys, ZhenZhen Liu, Ward Capoen, Angeliki Asimaki, Jason R Becker, Eddie Adams, Andre G Kleber, Jeffrey E Saffitz, Calum A MacRae
Journal: Circulation (2012)

Introduction: The arrhythmogenic cardiomyopathies (ACs) are rare inherited heart muscle disorders with a high incidence of ventricular tachyarrhythmias and sudden death. One prominent feature of ACs is variable penetrance that implicates major genetic and epigenetic modifiers of disease expression. We sought to develop a robust model of AC in the zebrafish to enable high-throughput genetic and chemical screens for important modifier pathways in ACs. Methods and Results: We generated a zebrafish AC model using cardiac-specific expression of the 2057del2 mutation in human plakoglobin using the GAL4/UAS transactivation system. Plakoglobin mutant fish exhibit a unique phenotype with mild bradycardia, cardiomegaly, and peripheral edema in early adulthood and substantial mortality by the time maturity is reached (survival 45% vs 77% for WT p&lt;0.01). Using qPCR we confirmed an upregulation of natriuretic peptide b (nppb), in mutant expressing fish compared to non-expressing siblings (2 fold, p&lt;0.01). To adapt this line for high-throughput screening, we mated the founders with an existing nppb:luciferase reporter line that we have previously validated and is compatible with 96-well plates. Native nppb expression was strongly correlated with semi-automated luciferase data in this reporter line (average count/embryo ± SEM 202 ± 15 in mutant vs 117 ± 12 in WT, P&lt;0.001). We have gone on to screen a library of 4800 bioactive compounds for disease modifiers and to date have identified both suppressor compounds (10) and compounds that exacerbate the disease response (14). One suppressor of the disease phenotype (SB2) attenuates nppb expression, bradycardia and contractility in the mutant, while also improving survival at 28 days (survival 1.5 μ M SB2 62% and 74% 3 μ M SB2 vs untreated 46%, p&lt;0.01). Conclusion: These data support the feasibility of high-throughput approaches to the modeling of complex cardiovascular disorders in zebrafish, as well as the use of such models to identify novel chemical probes and candidate drug leads for major disease pathways. One compound identified in the screen has already demonstrated efficacy in long-term use in AC models. Ultimately, screens of type will enable personalized disease modeling for a broad range of human diseases.
Abstract 19196: Resveratrol Prevents the Oxidative Stress and Diastolic Dysfunction in Iron-overload Cardiomyopathy
Authors: Subhash K Das, Vaibhav B Patel, Seyyed M.R. Kazemi-Bajestani, Pavel Zhabyeyev, Jason R Dyck, Gavin Y Oudit
Journal: Circulation (2012)

Introduction: Iron-overload cardiomyopathy results in heart failure with high morbidity and mortality. Iron-overload results in iron-induced oxidative stress and organ dysfunction and is associated with genetic and acquired iron-overload conditions. Resveratrol is a natural polyphenol with a broad range therapeutic potential. Hypothesis: We hypothesized that resveratrol will reduce iron-induced oxidative stress and prevent iron-overload cardiomyopathy. Methods and Results: Iron-overload cardiomyopathy was induced by treating 10 week old male C57Bl6 mice sub-acutely with iron-dextran at 5 mg/25g body weight i.p, 5 days/week for 4 weeks. The antioxidant and metabolic modulator, resveratrol was given at 190 mg/kg/day. Quantification of tissue iron showed significant deposition in the heart (350±27 vs 5304±773 µg/mg tissue; n=10, p&lt;0.01) which was confirmed by Prussian blue staining. Hemodynamic (+dP/dt/-dP/dt max ratio=1.0 vs 1.7; n=6) and echocardiographic (E/A ratio: 1.46±0.043 vs 1.27±0.06, n=6, p&lt;0.05; E’/A’ ratio: 0.77±0.04 vs 1.20±0.05, n=7, p&lt;0.01) analysis showed diastolic dysfunction with preserved systolic function in iron-overload hearts in the absence of increased myocardial fibrosis. Resveratrol treatment prevented the development of diastolic dysfunction (E/A ratio:1.27±0.06 vs 1.67±0.13 and E’/A’:1.2±0.05 vs 0.80±0.02; n=7, p&lt; 0.01; hemodynamic: +dP/dt/-dP/dt ratio: 1.6 vs 1.1 n=6, p&lt;0.01) without altering the degree of iron-overload (5200±743 µg/mg tissue ; n=10). Increased expression of ANF (65%), BNP (103%) and β-MHC (44%) showed a complete normalization with resveratrol treatment. Expression of oxidative stress-related genes, thioredoxin (91%), catalase (140%), glutathione peroxidase (548%) and superoxide dismutase (87%) were increased in iron-overload mice treated with resveratrol with a complete normalization of reduced glutathione levels in the heart (GSH: 50 vs 250ng/mg tissue). Conclusions: Iron-overload resulted in oxidative stress mediated selective diastolic dysfunction with preserved systolic function. Treatment with resveratrol can prevent oxidative stress and myocardial injury and protect the heart from the iron-overload induced diastolic dysfunction.