tbuckley/cabot-search huggingface dataset:
Abstract 581: Rapid Down-Regulation of Connexin43 after Stretch-Induced Early Myocardial Hypertrophy
Authors: Tepmanas Bupha-Intr, Kenneth D Varian, Paul M Janssen
Journal: Circulation (2006)

Gap junctions are important for cardiac conduction and consequent synchronized contraction. Heterogeneous gap junction distribution or reduced numbers of gap junctions can cause arrythmogenic components in hypertrophic cardiomyopathy. It is known that during end stage failure expression of critical gap junction proteins are down-regulated. It is unknown if in early stages of hypertrophy, mechanical load plays a role in reduction of gap junction protein levels. To assess the hypothesis that regulation of connexin43 expression occurs during early stage of hypertrophic induction, expression was measured in cultured multicellular myocardium subjected to high mechanical loading. Right ventricular trabeculae from rabbit hearts were subjected to high mechanical load or no load (slack) conditions in a multicellular muscle culture system. These small ventricular trabeculae were continuously electrically stimulated at 1 Hz at 37 Celsius, and isometric contractions were recorded for periods 24 – 48 hours. Muscles exposed to high load gradually increased developed force with time. Average developed force measured at 24 h was 178 +/− 22 % (n=12, P&lt;0.05) from starting values. We observed a significant increase in muscle diameter, by 4.3 +/− 1.4 (n=8, P&lt;0.05) and 17.4 +/− 3.7 % (n=14, P&lt;0.05) after 24 and 48 hours of high load contractions. Edema was absent, indicating myocyte hypertrophy. Protein quantification showed a down-regulation of connexin43 in stretched muscles to 49 +/− 14% (n=5, P&lt;0.05) and 31 +/− 10% (n=5, P&lt;0.05) of control fresh muscles after 24 and 48 h of high load, respectively. There was no significant different in connexin43 expression between fresh control myocardium and muscles cultured and stimulated in absence of load for 48 hours. Reduced connexin43 levels resulted in a functional impairment of gap junctions. Only in non-stretched muscles iontophoretically loaded bis-fura 2 into a single central myocyte could spread form cell to cell with a good success rate (~80 –90%). Out of 8 high load muscles we were able to spread dye via gap junctions in only a single muscle, and this only at levels well below normal. We conclude that mechanical loading alone can decrease expression and function of gap junctions during early cardiac hypertrophy.
Abstract 4866: Red Blood Cell and Mixed Types of Aspirated Intracoronary Thrombi Obtained From Patients With Acute Myocardial Infarction Predict Long-Term Mortality
Authors: Kei Yunoki, Takahiko Naruko, Ryushi Komatsu, Nobuyuki Shirai, Masashi Nakagawa, Kenichi Sugioka, Yoshihiro Ikura, Kengo F Kusano, Akira Itoh, Kazuo Haze, Makiko Ueda
Journal: Circulation (2009)

Background: Oxidative stress and inflammatory processes are of major importance in plaque instability. We demonstrated previously that elevated plasma oxidized low-density lipoprotein (ox-LDL) levels are related to plaque instability. In this study, we investigated whether plasma ox-LDL levels were related to the types of intracoronary thrombi (ICT) obtained by percutaneous thrombectomy in 130 patients within 12 hours of onset of acute myocardial infarction (AMI). We also analyzed whether individual types of ICT were related to long-term mortality. Methods: Frozen samples of aspirated ICT from 130 AMI patients were studied. Serial sections were investigated immunohistochemically using antibodies against platelets, red blood cells (RBCs) (glycophorin A) and neutrophils (CD66b and MPO). The ICT were classified into three types: platelet (PL) type (&gt;70% of the ICT surface area consisting of platelets; n=45), RBC type (&gt;70% of the ICT surface area consisting of RBCs; n=31) or mixed type (mixture of platelets and RBCs; n=54). We also measured plasma ox-LDL levels on admission using a specific monoclonal antibody. Results: Plasma ox-LDL levels were significantly higher in the RBC type than in the PL type (RBC, 1.89±1.84; mixed, 1.35±1.21; PL, 1.01±0.94 ng/5 μ g LDL protein; RBC versus PL, P&lt;0.05). Quantitative analysis demonstrated the percentage of MPO-positive neutrophils in the RBC or mixed types were significantly higher than in the PL type (RBC, 35±16%; mixed, 36±18%; PL, 23±17%; RBC versus PL, P&lt;0.05 and mixed versus PL, P&lt;0.005). Over a mean follow-up period of 33.5 months (range 1 day – 87.6 months), there were 17 cases (13%) of cardiac death. Kaplan-Meier survival curves showed that RBC and mixed types had significantly worse mortality than the PL type (P=0.040 by log-rank test). Multivariate analysis demonstrated that RBC and mixed types were independent determinants of long-term mortality (OR, 5.34; 95%CI, 1.083 – 26.37, P=0.039). Conclusions: The present study demonstrates that neutrophil activation and MPO release in mixed or RBC types of thrombi may play a role in generating excessive pro-oxidants. In addition, the presence of thrombi with RBC and mixed types is an independent predictor of long-term mortality.
Abstract 5012: Metabolic Syndrome Associates With Resistance to Aspirin in Patients With Coronary Artery Disease
Authors: James P Smith, Elias V Haddad, Olivier Boutaud, Denise A Oram, Dana L Blakemore, Qingxia Chen, Mary B Taylor, John A Oates
Journal: Circulation (2009)

The ability of aspirin to acetylate cyclooxygenase (COX) ex vivo depends on the oxidation state of the enzyme. This suggests that clinical phenotypes associated with increased endogenous platelet activation, which generates lipid hydroperoxides in the platelet, may impair aspirin’s efficacy. Accordingly, we hypothesized that resistance to aspirin would be associated with metabolic syndrome based on evidence for increased in vivo platelet activation in this condition. We prospectively enrolled patients with coronary artery disease (CAD), who were taking aspirin as part of their outpatient regimen, and provided aspirin 81mg daily for 2 weeks. We optimized compliance with a telephone call mid-study and a pill count. The primary outcome was serum thromboxane B 2 (sTxB 2 ) measured by GC/MS, which reflects aspirin’s pharmacological effect. Of 137 patients who completed the study with sufficient data for analysis, the mean age was 65±9 y, blood pressure 126/73, and body mass index 30±5.7 kg/m 2 ; nearly all (99%) had a diagnosis of hypertension and 39 (29%) were diabetic. Ninety (66%) received enteric-coated aspirin (ECASA) and 47 (34%) received chewable aspirin. Twelve patients with sTxB 2 &gt;13ng/ml were characterized as resistant to aspirin, as this represented &lt;95% inhibition of the mean sTxB 2 levels determined in 60 aspirin-naïve healthy volunteers. All of these resistant patients had metabolic syndrome as defined by the AHA. Exploring this association further in a linear model, we found that the presence of metabolic syndrome significantly associated with higher sTxB 2 (log-transformed) (P=0.011), adjusted for age, sex, and formulation of aspirin. In a second linear model, no significant associations were found with the individual components of the metabolic syndrome, indicating that the presence of these components in concert was required to predict incomplete response to aspirin. Although the use of ECASA associated with higher sTxB 2 in both linear models (P=0.013), the formulation of aspirin did not correlate with sTxB 2 &gt; 13ng/ml. These data suggest that the metabolic syndrome contributes to inadequate platelet inhibition by aspirin in patients with CAD.
Abstract 4205: Cardiovascular Risk Profiles Measured at the Same Age in American Immigrant Fathers and Offspring
Authors: Beatriz L Rodriguez, John S Grove, Kamal H Masaki, Timothy A Donlon, Randi Chen, Todd Seto, Thomas Quertermous, J D Curb
Journal: Circulation (2006)

The changes in risk profiles which occur with immigration to new cultural environments are well known. However, there have been few instances where the magnitude of these changes can be examined by measurements of cardiovascular risk factors in parents and offspring at the same age. Vital statistics indicate that Japanese-Americans in Hawaii have substantially lower CVD (cardiovascular disease) rates than are present in U.S. Caucasians, but markedly higher rates than those seen in Japanese in Japan. The Honolulu Heart Program (HHP) first measured CVD risk in first and second generation Japanese-American men in Hawaii from 1965 to 1968. From 2001 to 2004, similar measures were made in offspring from a random sample of families of these HHP men as part of the NHLBI Family Blood Pressure Program. This analysis uses data from 987 offspring (505 male and 482 female) between 39 to 77 years of age. At the time of examination, the mean age for the fathers was 53.7 years and for the offspring was 56.5 years. For some risk factors, the offspring had lower age-adjusted mean values than their fathers. The mean total cholesterol in the fathers was 218 mg/dl compared to 198.9 mg/dl in sons [p&lt;0.001] and 212 mg/dl in daughters [p&lt;0.001]. Current smoking was seen in 38% of fathers as compared to 15% of sons [p&lt;0.001] and 8% of daughters [p&lt;0.001]. However, for other risk factors, the offspring levels were higher. Hypertension (BP &lt;140/90 or on meds) was present in 39% of fathers as compared to 51% of sons [p&lt;0.001] and 43% of daughters [ns, p=0.27]. The fathers were much leaner, with an age-adjusted mean Body Mass Index (BMI) of 23.9, compared to 27.2 for sons [p&lt;0.0001] and 25.5 for daughters [p&lt;0.0001]. Although defined in slightly different ways in fathers vs. offspring, diabetes was present in 15% of fathers as compared to 24% of sons [p&lt;0.01] and 17% of daughters [ns, p=0.59]. While one must consider temporal trends as well as acculturation in making these comparisons, these data offer remarkable insight into changes in cardiovascular risk which immigrant populations face in the U.S. today.
Abstract 572: Deletion of iNOS in Mice Overexpressing Calcineurin Improves Cardiovascular Phenotype
Authors: Julie R Somers, James P Lees-Miller, Paul L Beck, Henry J Duff
Journal: Circulation (2006)

Previous studies have reported that overexpression of calcineurin (CN) in mouse myocytes produces cardiac hypertrophy followed by dilation, systolic dysfunction, cardiac fibrosis and sudden cardiac death due to high degree heart block and eventual asystole. In a number of cell types, calcineurin mediates iNOS expression. Since overexpression of iNOS in mice generates phenotypes quite similar to that seen in calcineurin mice, we assessed the hypothesis that deletion of iNOS (iNOS null mice) would improve the cardiovascular phenotype of mice transgenically overexpressing CN. Methods: A complementary breeding program generated CN/iNOS −/− mice. These were compared to CN mice. Results: Similarities exist between the two groups of mice: indices of cardiac hypertrophy as assessed by echocardiography (septal and posterior wall dimension and LV mass index) and heart weight/body weight index were similar. The histologic extent of fibrosis (Masson trichrome) was similar, as was the frequency of episodes of ventricular tachycardia on telemetry monitoring at 14 weeks. However, significant differences were also noted. CN/iNOS −/− mice had significantly greater survival (Kaplan Meier p&lt;0.0003). Fifty percent of CN mice die by 19 weeks compared to 34 weeks in CN/iNOS −/− mice. In addition, at 14 weeks CN/iNOS −/− mice had fewer episodes of high degree AV block; significant and substantial improvements in metrics of systolic wall motion (fractional shortening, LV internal dimension at the end of systole); smaller serum concentrations of TNFα; less interstitial apoptosis as assessed by Tunnel staining; and increased responsiveness of contractility to β1 stimulation with isoproterenol. Activation of iNOS in CN transgenic mice contributes to the cardiovascular phenotypes. Conclusion: While iNOS deletion almost doubles survival and improves most metrics of cardiovascular performance at 14 weeks, it delays, but does not abrogate the consequences of overexpressing calcineurin.
Abstract 4954: A Novel Role of CCN3 in Regulating Endothelial Inflammation
Authors: Zhiyong Lin, Viswanath Natesan, Hong Shi, Anne Hamik, Daiji Kawanami, Caili Hao, Ganapati H Mahabaleshwar, G. Brandon Atkins, Laure Rittié, Sue M Firth, Bernard Perbal, Mukesh K Jain
Journal: Circulation (2009)

Background : The vascular endothelium plays a fundamental role in the health and disease of the cardiovascular system. However, the molecular mechanisms regulating endothelial homeostasis remain incompletely understood. CCN3, a member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators, has been shown to play an important role in numerous cell types. While CCN3 expression in endothelial cells has been described, its function in this cell type has yet to be elucidated. Methods and Results : A detailed immunohistochemical analysis of CCN3 expression in mouse tissues revealed robust immunoreactivity in the endothelium of large arteries, small resistance vessels, as well as veins. Likewise, CCN3 expression is observed in cultured human endothelial cells derived from a variety of vascular beds. CCN3 expression in human umbilical vein endothelial cells (HUVECs) is transcriptionally induced by laminar shear stress (LSS) by ~27-fold. Similarly, treatment of HUVEC with HMG CoA-reductase inhibitors (statins) induced CCN3 expression by ~32-fold. A combination of promoter deletion and mutational analyses coupled with chromatin immuno-precipitation studies identified the Kruppel-like factor 2 as a direct regulator of CCN3 expression. In contrast to LSS, proinflammatory cytokines such as TNF α reduced CCN3 expression. Functionally, adenoviral overexpression of CCN3 in HUVEC markedly inhibited the cytokine-mediated induction of VCAM-1. Consistent with this observation, CCN3 overexpression significantly reduced monocyte adhesion. Conversely, siRNA mediated “knockdown” of CCN3 protein in HUVECs resulted in enhancement of cytokine-induced VCAM-1 expression. Concordant effects were observed on monocyte adhesion. Mechanistically, gain and loss-of-function studies demonstrate that CCN3 negatively regulates NF- κ B activity by reducing its translocation into nucleus and DNA binding to VCAM-1 promoter, suggesting that CCN3’s anti-inflammatory effects occur secondary to inhibition of NF- κ B nuclear accumulation. Conclusions: This study identifies CCN3 as a novel regulator of endothelial proinflammatory activation.
Abstract 4902: Renal Sinus Fat Influences the Number of Medications Needed to Regulate Blood Pressure in Patients With Hypertension
Authors: Haroon L Chughtai, Tim M Morgan, Jingzhong Ding, Tina E Brinkley, Michael Rocco, Craig A Hamilton, W. G Hundley
Journal: Circulation (2009)

Introduction: A potential consequence of increasing intraperitoneal (IP) fat is the accumulation of fat in the renal sinus (RS). Compression of low pressure vessels (renal veins, lymphatics), by RS fat may result in activation of the renin-angiotensin system (RAS) and promote more extensive use of antihypertensive therapy. Hypothesis: RS fat would be associated with IP fat and number of medications for blood pressure control. Methods: Two hundred five participants aged 55 to 85 years, without renal artery stenosis, underwent magnetic resonance imaging measures of RS and abdominal fat (subcutaneous + IP + retroperitoneal). Data were analyzed for possible associations of RS fat with renal function, BP, and the number of prescribed antihypertensives. Results: Age averaged 69 ± 9 years; 50% were women. RS fat averaged 5 ± 3 cm 3 (up to 16 cm3). RS fat correlated with retroperitoneal and IP fat volumes, and cardiac risk factors (hypertension, diabetes, and coronary artery disease) (r = 0.49, 0.42, and r = 0.18, p = 0.001, 0.001, and 0.009 respectively); it did not correlate with subcutaneous fat (r = −0.08, p = 0.23). RS fat also showed a positive association with number of antihypertensive medications, renal size, creatinine, pulse pressure, and an inverse correlation with serum potassium, a marker of RAS activation (r = 0.21, 0.44, 0.23, 0.13, and 0.16; r = −0.18, p = 0.01) [Table ]. These associations of RS fat persisted after adjustment for age, gender, height, diabetes, coronary artery disease, serum lipids, and IP fat (p = 0.01 for all). Importantly, after adjusting IP fat to RS fat in our regression model, RS fat remained associated with the number of prescribed anti-hypertensive medications ( B = 0.27, p = 0.01), while IP fat did not. Conclusions: Higher volumes of renal sinus fat are associated with indirect evidence of the activation of the RAS and the number of medications used to treat hypertension. These data suggest a possible mechanism for central obesity to promote hypertension. Table: Correlations of different variables using renal sinus fat as a dependant variable
Abstract 186: Biopacemakers Induced by Gene Transfer of a Dual-Functional Kir2.1 Mutant
Authors: Yuji Kashiwakura, Kuan-Cheng Chang, Yiqiang Zhang, Andreas Barth, Hee Cheol Cho, Tetsuo Sasano, Eduardo Marbán
Journal: Circulation (2006)

Previous efforts to engineer biopacemakers have focused either on overexpression of HCN, or on suppression of I K1 to liberate endogenous pacemaker activity. Here we report a novel strategy designed to convert I K1 into a nonselective “leak” current. The idea is to combine the key virtues of HCN (leak current) and I K1 suppression (destabilization of the resting potential) in a single gene construct. We focused on the human Kir2.1ER mutation (E138R and R148E, KER) which can work as not only a functional non-selective channel in homotetramers but also as a dominant-negative suppressor for the Kir2.X gene family in heart. The plasmid CMV-KER-IRES-wtKir2.1 coexpresses the KER mutant and wild-type Kir2.1. In HEK cells transduced with CMV-KER-IRES-wtKir2.1, barium sensitive hyperpolarization-activated inward current (−5.5 pA/pF at −80mV) could be detected (n=5) with a reversal potential of −35.1± 2.1 mV in normal Tyrode external solution. These data demonstrate that overexpression of KER undermines the ability of Kir to produce functional I K1 channels, while producing a cation-nonselective leak current. To probe the consequences of KER in primary tissues, we created the adenovirus AdKER in which KER expression is driven by the CMV promoter. Isolated guinea-pig myocytes transduced with AdKER exhibited spontaneous action potential oscillations with high reproducibility (n=10). Electrocardiograms performed 3 days after AdKER injection into guinea pig hearts showed idioventricular rhythms in virus injected-animals, while no such rhythms were seen in control (AdGFP) animals (n=6 each). These results show that KER mutants, if expressed in ventricular muscle, produce biopacemakers in vitro and in vivo . This study provides proof of principle for the notion that biological pacemakers can be readily induced by a single gene designed to destabilize I K1 and to create a leak current.
Abstract 4910: Forkhead Transcription Factor 3a (FOXO3a) is Involved in the Regulation of Functional Response to Aging and Stress in Murine Cardiomyocytes
Authors: Qun Li, Heng Ma, Paul Thomas, Machender R Kandadi, Jun Ren
Journal: Circulation (2009)

Aging is a complicated but regulated process. Forkhead transcription factors (FOXO), the major substrates for the protein kinase Akt and AMP-activated protein kinase, play an important role in longevity. Our earlier studies suggested that deficiency in insulin-growth factor I (IGF-1) contribute to cardiomyocyte dysfunction but prolongs lifespan possibly through downregulation of FOXO3a signaling. Given that lifespan extension is closely associated with stress tolerance, our present study was set to examine the effect of FOXO3a inhibition on aging-/stress-induced cardiomyocyte contractility and survival. The dominant negative FOXO3a-GFP adenovirus was injected into adult and aged C57BL/6J murine hearts. Five days later, GFP positive cardiomyocytes (denoting successful Foxo3a transfection) isolated from in adult and old C57BL/6J mice were identified for assessment of contractile properties including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR 90 ), and maximal velocity of shortening/relengthening (+/−dL/dt). Dominant negative FOXO3a (FDN) transfection significantly reduced PS in adult group although it restored aging-induced dysfunction in PS, +/−dL/dt and TR 90 . Further study on MTT assay and western blot revealed that transfection of FDN in H9c2 myoblasts exhibited higher survival rate in response to paraquat and H 2 O 2 compared to control group. Inhibition of FOXO3a expression enhanced phosphorylation of Akt and AMPK in both normal and paraquat-treated conditions. Paraquat downregulated the “aging” protein-klotho, the effect of which was restored by FDN transfection. These data suggested that FOXO3a plays an important role in regulation of cardiomyocyte contractility and stress resistance under aging or oxidative stress.
Abstract 4169: Decreased Serum Ghrelin Level in Patients with Acute Myocardial Infarction: Its Association with the Infarct Size and Left Ventricular Dysfunction
Authors: Satoshi Yasuda, Shunichi Miyazaki, Hiroshi Hosoda, Noritoshi Nagaya, Yu Kataoka, Isao Morii, Atsushi Kawamura, Hiroshi Nonogi, Kenji Kangawa
Journal: Circulation (2006)

Background : Ghrelin, a circulating brain-gut peptide, has been identified as potent ligand for the growth-hormone secretagogues receptor, distributed in cardiovascular system. Experimental studies demonstrated that ghrelin has protective effects against ischemia-reperfusion injury and apoptosis. Therefore, the present study was designed to investigate the role of ghrelin in patients with acute myocardial infarction (AMI). Methods : Forty-six patients were studied and divided into the following four groups; 16 patients with AMI (M/F=15/1, 67±10[mean±SD]years, body mass index (BMI, kg/m 2 ; 23±2), 12 patients with unstable angina pectoris (uAP: M/F=9/3, 64±5years, BMI;23±2), 13 patients with stable AP (sAP: M/F=12/1, 66±6years, BMI;22±2) and 5 control patients with chest pain without any coronary artery disease (M/F=4/1, 66±5years, BMI; 23±2). Serum ghrelin level was measured by newly developed enzyme immunoassay system (MM-402, Mitsubishi Kagaku Medical Inc.). The sensitivity of this system is 2.5fmol/mL. Results : In comparison with control, sAP and uAP patients, serum ghrelin levels were significantly decreased on day 0 (on admission) in AMI patients. In next two weeks, ghrelin levels recovered with a time-dependent trend (P&lt;0.01). In patients with AMI, serum level on day 14 divided by that on day 0, an index of MI-related acute change in ghrelin, correlated positively with peak creatinine phosphokinase level (R=0.74, P&lt;0.01) and negatively with left ventricular ejection fraction (R=-0.53, P&lt;0.05). Conclusions : In patients with AMI, secretion of ghrelin is suppressed in association with a large infarct size and left ventricular dysfunction. Considering cardioprotective effect of ghrelin, its exogenous administration will provide new perspective for AMI treatment. Serum ghrelin levels (*P&lt;0.05 vs AMI day 0)