tbuckley/cabot-search huggingface dataset:
Abstract 16814: A miRNA Signature of the Failing Right Ventricle
Authors: Roxane Paulin, Gopinath Sutendra, Peter Dromparis, Sebastien Bonnet, Evangelos Michelakis
Journal: Circulation (2011)

INTRODUCTION: Right Ventricular Failure (RVF) is the most important prognostic structure for both morbidity and mortality in pulmonary hypertension (PHT) but remains understudied compared to the left ventricle (LV). Many differences (including embryologic origin) separate the 2 ventricles and the transition from a compensated to decompensated stage occurs much earlier in the RV vs the LV, in response to pressure overload. MicroRNAs (miRNAs) have emerged as important determinants of LV development and failure, but nothing is known about RV miRNAs. We hypothesized that specific miRNAs signatures may characterize the transition from the fetal to adult and from a compensated (CRV) to a decompensated (DRV) RV. METHODS/RESULTS: We studied free RV wall tissue from neonatal (Neo) and rats with normal RV function (NRV, RVSP=38±2 mmHg, CO=102±2 ml/min and RV/LV+Septum=22±1), CRV (RVSP=66±8 mmHg, CO=80±13 ml/min, RV/LV+Septum=48±3, 2-3 weeks post-monocrotaline) and DRV (RVSP=52±2 mmHg, CO=67±10 ml/min, RV/LV+Septum=58±2, ascites, weight loss, 4-6 weeks post monocrotaline) (n=6 in each group). We used Taqman Low Density Arrays to study the expression of 377 miRNAs. Neonates were separated clearly from other samples in both principal component analysis and hierarchical clustering analysis. 14 miRNAs were identified as differentially expressed between CRV, DRV and NRV (ANOVA applied on fold-change obtained after standard normalization procedures were performed (U6, median, quantile)). Among them, 7 showed a different pattern of expression compared to published data on LV hypertrophy: miR-200b, -132, -338-3p, -328, -155, -92a and -208. miR-208 has received attention as critical regulator of LVH. We showed that 208 decreased in CRV and DRV compared to NRV, whereas its expression is not known to decrease in LVH. This was confirmed by individual qRT-PCR and miR-208 levels were also found to negatively correlate with RV size (r=-0.72, n=20, p&lt;0.001) as failure progresses. CONCLUSION: Further exploration of this unique miRNA signature, compared to LV, may also open new avenues of investigation on RVF. Since miR-208 is cardiac specific and regulated differently compared to LVH, it may offer important clues on why the RV responds suboptimally to pressure overload.
Abstract 18646: The Dynamic Relationship Between GRK2 and NOS/NO Critically Determines Cardiac Ischemia/Reperfusion Injury
Authors: Z. Maggie Huang, Erhe Gao, Xiying Shang, Xufan Tian, Gang Qiu, J Kurt Chuprun, Hiroki Hayashi, Douglas T Hess, David J Lefer, Jonathan S Stamler, Walter J Koch
Journal: Circulation (2012)

Background and Aim s: G protein-coupled receptor kinase 2 (GRK2) and endothelial nitric oxide synthase (eNOS) play key roles in cardiac signaling and function. Increased GRK2, seen in injured myocardium, causes increased cell death and injury after ischemia while reciprocally, eNOS/NO exerts protection. A link between these two systems occurs as GRK2 can be regulated via S-nitrosylation (SNO) at Cys340, which inhibits its activity. Alternatively, increased GRK2 activity inhibits NO in the heart. The aim of this study was to determine whether there is a dynamic interaction between cardiac GRK2 and eNOS/NO. Methods: We investigated a direct interaction between GRK2 and eNOS in cultured myocytes and hearts. Cardiac-specific transgenic mice overexpressing GRK2 (Tg-GRK2) and mice with expression of the GRK2 inhibitor βARKct (Tg-βARKct) were used to create hybrid mice with concurrent modulation of eNOS. Finally, we created novel knock-in mice where all endogenous GRK2 was a mutant form (Cys340Ser) resistant to SNO regulation. All mice were characterized basally and subjected to ischemia/reperfusion (I/R) injury and infarct size and cardiac phenotypes determined. Results: 1). Co-immunoprecipitation discovered an interaction between GRK2 and eNOS in cardiac tissue, which was significantly increased in the ischemic heart. 2). TgGRK2/TgeNOS hybrid mice showed significantly reduced infarct size and improved function post I/R compared to Tg-GRK2 mice. Protection offered by βARKct was reversed in mice without eNOS. 3). SNO-GRK2 was increased by isoproterenol and GSNO in WT mice but was not observed in GRK2-C340S mice. 4). Interestingly, GRK2-C340S mice exhibited significantly larger injury post I/R compared to WT mice with decreased cardiac dysfunction. GSNO treatment reduced infarct size in WT mice but had no effects in GRK2-C340S mice. Also, pre-treatment with the NOS inhibitor L-NAME increased infarct size in WT mice but not in GRK2-C340S mice. Conclusions: Our data demonstrates a unique relationship between GRK2 and NO signaling in the heart, which has direct implications for mechanisms of cardiac injury. This includes the demonstration that GRK2 is a nodal pro-death kinase after I/R injury and its SNO is a requirement for NO-mediated cardioprotection.
Abstract 174: Cardiotoxic Neighborhoods: Marked Variations in Domiciles of Victims of Cardiac Arrest Within a Large Urban Area
Authors: Katherine S Allan, Joel G Ray, Peter Gozdyra, Alex Kiss, Laurie J Morrison, Jason E Buick, Cathy Zhan, Matthew Guttman, Paul Dorian
Journal: Circulation (2011)

Introduction: Out of hospital cardiac arrest (OHCA) incidence rates may vary across regions. Prior studies measured OHCA variability by the location of the OHCA, rather than the victim's place of residence, thereby omitting potentially important demographic predictors of OHCA. Objectives: To measure variability of OHCA rates by residential address within a large urban centre, and the characteristics of persons living in areas that are associated with a higher rate of OHCA. Methods: We included 5656 adults aged 20+ y who experienced an OHCA in Toronto, Canada from 2006-2010. Each OHCA patient's home address was spatially mapped to 1 of 527 census tracts (CT). In order to assess variability we conducted (1) point cluster analysis using SatScan software, which identified areas with significantly higher counts of OHCA; (2) Poisson regression models were used to assess the OHCA relative risk (RR) by CT (after adjusting for age and sex); (3) We assessed the relationship between OHCA rates and socioeconomic (SES) variables within each CT. Results: Incidence of OHCA varied widely by CT (Figure 1). Adjustment for age and sex did not alter this variation. Cluster analysis identified 4 geographically distinct areas where there was higher risk of OHCA compared to adjacent CTs. With respect to SES variables, CTs with a higher median household income had a lower risk of OHCA (RR 0.98 per $10000 increase in income, 99% CI 0.95-1.00), as did CTs with higher education status (RR 0.996 per 1% increase in education, 99% CI 0.992-0.999). CTs with a higher percentage of South Asians (SA) were not at higher risk of OHCA (RR 1.003 per 1% increase in SA population, 99% CI 0.997-1.009), but those with a higher percentage of Afro-Caribbeans (AC) were (RR 1.007 per 1% increase in AC population, 99% CI 1.002-1.013). Conclusions: The risk of OHCA varies by the features of one's place of residence. Further study is required to investigate possible causes for these variations.
Abstract 18654: Impaired Coronary Microvascular Function is Independently Associated with Fatal Cardiac Events at Long-term Follow-Up in Patients with Stable Coronary Artery Disease
Authors: Tim P van de Hoef, Matthijs Bax, Peter Damman, Ronak Delewi, Mariëlla E Hassell, Steven A Chamuleau, Michiel Voskuil, Jan G Tijssen, Jan J Piek, Martijn Meuwissen
Journal: Circulation (2012)

Background: Coronary microvascular dysfunction is increasingly recognized as an elementary component in the spectrum of coronary artery disease. Coronary flow velocity reserve (CFVR) is importantly determined by microvascular function, and may be considered a direct measure of microvascular function when measured in a reference coronary artery. We sought to determine the prognostic value of microvascular function, as assessed by measuring reference vessel CFVR (refCFVR), for long-term cardiac mortality. Methods: We studied consecutive patients with stable coronary artery disease in whom refCFVR was measured between April 1997 and September 2006 as part of ongoing study protocols. Patients underwent PCI of all ischemia causing lesions, as assessed by myocardial perfusion scintigraphy. Long term follow up was performed to document the occurrence of cardiac death. Results: RefCFVR was determined in 178 patients. During a median follow up of 11.6 years, 38 patients (15%) died of a cardiac cause. Kaplan Meier estimates of long term cardiac mortality showed a difference in mortality for high (≥3.0) and low (&lt;3.0) refCFVR values (Figure). RefCFVR was additionally shown to be independently associated with cardiac mortality at long term follow up after multivariable adjustment (HR 0.432; 95% CI 0.213 - 0.876. P=0.02). Abnormal refCFVR was found to result from significantly lower baseline microvascular resistance, and a consequent increase in baseline flow velocity in patients with an abnormal refCFVR (6.96±2.54 mmHg/cm/s when refCFVR ≥3.0, versus 5.46±1.82 mmHg/cm/s when refCFVR &lt;3.0; P&lt;0.001). In contrast, hyperemic resistances, as well as flow velocities, were comparable between groups (P=NS for both). Conclusion: Impaired coronary microvascular is independently associated with long-term cardiac mortality in patients with stable coronary artery disease.
Abstract 240: AMSA Predicts Shock Success in Cardiac Arrest Patients with Different Transthoracic Impedance
Authors: Yongqin Li, Weilun Quan, Qing Tan, Gary Freeman, Wanchun Tang
Journal: Circulation (2011)

Introduction: Amplitude spectrum area (AMSA), which is calculated from the Fourier transformation of ventricular fibrillation (VF) waveforms, has shown its ability in predicting the likelihood of successful defibrillation and monitoring the effectiveness of chest compression [1-3]. In the present study, we retrospectively evaluated the reliability of AMSA in predicting shock success over entire transthoracic impedance (TTI) range in pre-hospital cardiac arrest victims. Methods ECG recordings, along with TTI measurements between two shocking pads, were collected from multiple emergency medical services (EMS) in the USA through a regular field case submission program sponsored by ZOLL Medical Corporation. All the EMSs in this study use ZOLL AED which employs current-based impedance compensation technique. AMSA was calculated based on a 1024 point ECG window ending at 0.5 sec before each shock attempt. Shock success was defined as an organized rhythm that was present for a minimum of 30 seconds, started within 60 seconds after the shock, and had a rate of 40 beats per minute or greater. Results: A total of 599 patients with witnessed rhythm of VF were included in the analyses. Only the first shock (120J) was analyzed. As shown in Figure 1, AMSA was significantly higher for successful shocks as compared with failed shocks in different TTI ranges. With an AMSA threshold of 8 mVHz, a large amount of unnecessary shocks (79.3%, 92.4% and 98.1%) were avoided with accuracy of 61.5%, 65.4% and 62.2% when TTI was low, normal and high, respectively. Logistic regression indicated that both AMSA (O.R. 1.19) and TTI (O.R. 0.99) were independent predictors for shock success, though, AMSA was a positive predictor and TTI was a negative predictor for shock success. Conclusion: In this patient population, AMSA was confirmed to be significantly higher in the presence of successful defibrillation over the entire TTI range. AMSA therefore can reliably predict shock outcome at different TTI ranges. References 1. Marn-Pernat A, Weil MH, Tang W, et al. Crit Care Med 2001,29(12): 2360-2365. 2. Povoas HP, Weil MH, Tang W, et al. Resuscitation 2002;53(1):77-82. 3. Li Y, Ristagno G, Bisera J, et al. Crit Care Med. 2008 Jan;36(1):211-5.
Abstract 8399: Circulating Mononuclear Cells with Class A Macrophage Scavenger Receptor Were Specifically Increased in Patients with Acute Coronary Syndrome
Authors: Masafumi Nakayama, Hisao Ogawa, Koichi Kaikita
Journal: Circulation (2011)

Objective: We previously remarked that class A macrophage scavenger receptor (SR-A), in peripheral blood mononuclear cells (PBMCs), was a candidate as a predictive marker for acute coronary syndrome (ACS) utilizing a gene chip microarray system. Herein, we examined SR-A levels in atherosclerotic lesions and in circulating monomuclear cells. Methods and Results: We obtained atherosclerotic lesion samples utilizing directional coronary atherectomies: 11 consecutive patients with unstable angina (UA); and, 13 consecutive patients with stable exertional angina (SEA). Immunohistochemical analyses revealed that SR-A was abundantly expressed in the macrophages of UA patients. SR-A mRNA levels of the atherosclerotic lesions in the UA patients and in the SEA patients were 3.8±1.5 and 1.0±0.6, respectively. SR-A mRNA levels of the coronary atherosclerotic lesions were significantly higher in the UA patients than in the SEA patients (p&lt;0.03). Utilizing flow cytometric analysis, PBMCs were collected from 255 subjects: 67 consecutive ACS patients; 87 consecutive SEA patients; and, 101 controls. The frequencies of CD14-positive PBMCs (monocytes), that stained for SR-A, were 1.9±1.6% , 0.7±0.5% , and 0.7±0.5%, respectively. The frequency of SR-A positive monocytes was significantly higher in the ACS Group than in either the SEA or Control Groups (p&lt;0.001); however, there were no significant differences between the Control and SEA Groups. There were no significant differences in the frequencies of SR-A positive monocytes between the patients with UA and the patients with acute myocardial infarction. In the ACS Group, the frequencies of SR-A positive monocytes at onset, at 1 day and at 7 days after onset, were 1.7±1.1%, 1.1±0.8%, and 1.1±0.5%, respectively. The frequency of SR-A positive monocytes in the ACS Group was significantly decreased within 24 hours of onset receiving orthodox medical treatment (p&lt;0.01). Conclusion: The SR-A level increases in unstable atherosclerotic plaque, as well as in the PBMCs in ACS patients. SR-A is a well known macrophage marker. The detection of SR-A positive monocytes in the peripheral circulating blood provides crucial clinically and pathophysiologicaly significant information about unstable plaque in ACS patients.
Abstract 18419: Depletion of Endothelial Progenitor Cells is Associated with Myocardial Dysfunction in Patients with Type 2 Diabetes Mellitus Without Coronary Artery Disease
Authors: Chunting Zhao, Mei Wang, Chong Wah Siu, Kai Hang Yiu, Hung Fat Tse
Journal: Circulation (2012)

Background: Patients with type 2 diabetes mellitus (T2DM) may develop cardiomyopathy and microvascular disease and oxidative stress may contribute to it. Endothelial progenitor cells (EPCs) is responsible for angiogenesis and has been shown to be closely correlated with oxidative stress. Accordingly, the aim of the study is to evaluate the role of EPCs and oxidative stress in relation with the left ventricular (LV) function in patients with T2DM. Methods: Ninety patients(62±9years, 39% male) with T2DM without coronary artery disease were recruited. Transthoracic echocardiography and detailed evaluation of LV systolic function by 2D speckle tracking derived strain analysis was performed. Four subpopulation of EPCs including CD34+, CD133+, CD34+/kinase insert domain-containing receptor (KDR) + and CD133+/KDR+ EPCs were measured by flow cytometry. Furthermore, oxidative stress was assessed by superoxide dismutase (SOD). Results: The mean HbA1c% was 7.76% and 18.9% were on insulin therapy. Global circumferential strain was associated with CD34+ EPCs (r=-0.22 , P=0.04) and SOD (r=-0.32 , P=0.01 ) but not the other EPCs. Patients were subsequently dichotomized according to the median level of CD34+ EPCs. The two groups of subjects had similar LV ejection fraction (63±7% vs. 65±8%, P=0.30). Importantly, patients with low level of CD34+EPCs had impaired LV global longitudinal strain (-16.7±2.7% vs. -18.1±2.2%, P&lt;0.01), circumferential strain (-17.2±2.1% vs. -18.3±2.2%, P=0.02) and radial strain (30.2±9.3% vs. 37.4±11.6%, P&lt;0.01) compared to those with high level of CD34+EPCs. After multivariate linear regression, CD34+ EPCs was an independent predictor of the circumferential strain (β=-0.22, 95%CI -25.2∼-0.70, P=0.04) and radial strain (β=0.27, 95%CI 17.2∼139.5, P=0.02). furthermore, SOD was an independent predictor of the circumferential strain (β=-0.32, 95%CI -13.7∼-1.7, P=0.01) Conclusions : Both CD34+ EPCs and SOD correlated with global circumferential strain. Importantly, the number of CD34+ EPCs and SOD is independently associated with LV systolic dysfunction in patients with T2DM. The present results thus suggested that EPCs and oxidative stress contributed to the development of diabetic cardiomyopathy.
Abstract 18936: Kidney Injury Molecule-1 (KIM-1) is a Promising Urinary Biomarker to Detect Cardiorenal Syndrome in Children with Dilated Cardiomyopathy (DCM)
Authors: Ahmad Kaddourah, Stuart Goldstein, John Jeffries
Journal: Circulation (2012)

Background: Type II cardiorenal syndrome (CRS) describes renal dysfunction in the presence of chronic heart dysfunction. Novel urinary acute kidney injury biomarkers (NUB) have not been studied in children with DCM. We aim to 1) Evaluate the correlation between four NUB and severity of LV dysfunction, and 2) Determine the best marker to detect CRS in children with DCM. Methods: We are conducting a cross-sectional study in children with DCM and LV dysfunction. Enrolled children had an echocardiogram to measure the LV ejection fraction (EF). Urine samples were collected at the same visit to measure the NUB: KIM-1, NGAL, IL-18, and L-FABP. NUB levels were adjusted for each mg of urinary creatinine. Glomerular filtration rate was estimated using modified Schwartz formula (eGFR) when Creatinine level (Cr) is available. Univariate analysis was conducted between patients (pts) with EF&lt; 45% and EF ≥ 45%. ROC analysis was performed for all NUB and GFR. 2x2 tables were constructed from NUB cutoffs to maximize specificity for EF &lt;45%. Results: 30 pts (14.2 ±6.4 years old) have been enrolled to date. 13 (43%) had EF&lt;45%. Although all NUB levels were higher in pts with EF &lt;45%, only KIM-1 was significantly higher [836.5 (±844.1) vs. 442.8 (±249.5) pg/mg cr , P one-tailed =0.04]. Area under the curve for KIM-1 was 0.61 to predict EF &lt;45%, compared to 0.53 for eGFR. A KIM-1 cutoff of 900 pg/mg cr yielded highest correct EF classification (38% sensitivity, 94% specificity). 6/30 (20%) pts had KIM-1 &gt;900; 5/6 (83%) had EF of &lt;45% vs. 8/24 (33%) with KIM-1&lt;900 (P one-tailed =0.03). Conclusions: Our pilot data suggest DCM pts with EF&lt;45% tend to have higher NUB urinary levels indicating worse CRS than pts with EF≥45%. Urinary KIM-1 may be the most predictive test to detect CRS compared to other NUB and eGFR. We anticipate confirming this finding by increasing the study’s power.
Abstract 18653: Decreased Levels of Circulating ‰Early Vascular Progenitor Cells are Associated with Cardiovascular Disease Risk
Authors: Natasha K DeJarnett, Daniel J Conklin, John A Myers, Ihab Hamzeh, Stephen Wagner, Timothy E O'Toole, Atul Chugh, Matthew Zahn, David J Tollerud, Andrew P DeFilippis, Deirdre Higdon, Carrie Becher, Bradley Wyatt, Tiffany Ciszewski, Daniel Riggs, James McCracken, Wesley Abplanalp, Sumanth D Prabhu, Aruni Bhatnagar
Journal: Circulation (2012)

Circulating levels of vascular progenitor cells (VPCs) have been suggested to be reflective of cardiovascular disease (CVD) risk. However, VPCs are a heterogeneous population containing cells with different angiogenic potential, and it is not clear which specific cell types are associated with CVD risk and specific CVD risk factors. We evaluated the relationship between CVD risk factors using antigenically-defined VPC sub-populations with or without validated angiogenic potential. Circulating VPC populations were measured in 240 high risk adults enrolled in the Louisville Healthy Heart Study. To quantify VPC levels, peripheral blood samples were stained with antigenic markers to define 6 different populations and analyzed using flow cytometry. CVD risk data were obtained from questionnaires, medical records, and blood/urine analyses. Generalized linear mixed-effects models were developed to examine the associations between mean VPC levels and the Framingham Risk Score (FRS) and CVD risk factors. A stepwise procedure was used to determine the most parsimonious model. The sample population was 54% male, 51±1 years old, 41% African-American, 39% current smokers, and had a mean FRS of 6±1. Levels of VPC subpopulations, VPC1 (CD31+/34+/45-), VPC3 (CD31+/34+/45-/AC133+), and VPC4 (CD31+/34+/45+/AC133+), significantly predicted FRS (β=-0.13 to -0.25; p=0.04 to 0.006) and showed stronger associations than previous reports using the entire VPC population. VPC2 (CD31+/34+/45+) and VPC6 (CD31+/34+) were not significantly associated with FRS. Moreover, VPC3 levels showed a strong positive association with circulating levels of platelet-leukocyte aggregates (CD41+/CD45+), whereas only the CD31+/AC133+ cells (VPC5) showed a negative association with LDL-C levels. None of the VPC sub-populations were correlated with serum fibrinogen or CRP levels. These observations indicate that immature (“early”) and non-monocytic (CD45-) VPCs levels are indicative of CVD risk and that the depletion of early VPCs (AC133+) may be reflective of a pro-thrombotic state and hypercholesterolemia but not systemic inflammation. Prospective longitudinal studies are required to assess the prognostic utility of measuring VPC subpopulations in peripheral blood.