tbuckley/cabot-search huggingface dataset:
Abstract 2571: Two-dimensional Ultrasound Speckle Tracking Imaging is Useful in Assessing the Magnitudes of Inertia Force of Late Systolic Aortic Flow and Left Ventricular Elastic Recoil
Authors: Kazuaki Wakami, Nobuyuki Ohte, Takahiro Nagata, Kaoru Asada, Hidekatsu Fukuta, Seiichiro Sakata, Seiji Mukai, Kenji Kobayashi, Genjiro Kimura
Journal: Circulation (2007)

We previously reported that an absence of inertia force (IF) of late systolic aortic flow is one of the causes of diastolic dysfunction through the loss of left ventricular (LV) elastic recoil in patients with coronary artery disease. Preserved LV apical wall motion is substantial to give IF to the aortic flow ( JACC 2006 ; 48 : 983 ). A novel 2-dimensional ultrasound speckle tracking imaging (2D-STI) enables us to assess local LV myocardial function. We investigated whether LV longitudinal systolic strain, especially in apical region, obtained using 2D-STI had a relation with IF. Methods: Study subjects were consecutive 59 patients who underwent diagnostic cardiac catheterization and 2D-STI (Velocity Vector Imaging, Siemens) on the same day. Thirty three of them had prior myocardial infarction (18 anterior wall, 9 infero-posterior wall, 2 lateral wall, and 4 combined). Five were diagnosed as dilated cardiomyopathy. The remaining 21 had no localized LV wall motion abnormality (8 stable angina pectoris, 2 exercise test abnormality, 2 atypical chest pain, and 9 reevaluation after coronary intervention). Longitudinal LV strain was measured on the sample line set along the endocardium in the both apical 4- and 2-chamber views. Zero strain was set at end-diastole. Strain profiles were obtained in 6 segments on each view. Then, an LV strain value at end-systole (Ses) in each patient was obtained as an average value from these strain profiles. LV pressure was obtained using a catheter-tipped micromanometer. From the recorded pressure waves, first derivative of LV pressure (dP/dt) and a time constant τof LV pressure decay during isovolumic relaxation were calculated. From LV pressure-dP/dt relationships (phase loop), IF was determined. Results: The mean Ses had significant correlations both with the time constant τ(r=-0.74, p&lt;0.0001) and with the IF (r=0.67, p&lt;0.0001). Furthermore, the mean Ses at the LV apical region had much closer correlations both with the time constant τ(r=-0.77, p&lt;0.0001) and with the IF (r=0.80, p&lt;0.0001). Conclusion: These findings indicate that the magnitudes of IF and LV elastic recoil could be noninvasively estaimated by Ses obtained using 2D-STI. LV apical wall motion abnormality has a strong impact on LV early diastolic function.
Abstract 340: Ablation of the Plasma Membrane Calcium ATPase 4 (PMCA4) Attenuates the Pressure Overload-Induced Hypertrophic Response and Protects against the Development of Left Ventricular Dysfunction
Authors: Delvac Oceandy, Min Zi, Sukhpal Prehar, Tamer Mohamed, Peter Stanley, Elizabeth Cartwright, Nasser Alatwi, Ludwig Neyses
Journal: Circulation (2007)

We have previously reported that isoform 4 of the plasma membrane calcium/calmodulin-dependent ATPase (PMCA4) interacts with and modulates neuronal nitric oxide synthase (nNOS) activity. Using transgenic mice overexpressing PMCA4 in the heart, we have demonstrated that the PMCA4-nNOS complex modulates cardiac contractility without altering global intracellular calcium transients ( Circulation 2007 ; 115 : 483 – 492 ). Here, we used PMCA4 knock out (PMCA4 −/− ) mice to test whether this novel signaling axis is involved in the regulation of mechanical stress-induced cardiac hypertrophy. PMCA4 −/− mice and wild type (WT) littermates were subjected to transverse aortic constriction (TAC) or sham operation. Five weeks after TAC, PMCA4 −/− mice showed a markedly reduced hypertrophic response compared to WT as indicated by left ventricular (LV) mass/tibia length ratio (table 1 ). Histological analysis demonstrated a significantly reduced cardiomyocytes cross sectional area in PMCA4 −/− TAC compared to WT-TAC. The activation of the fetal gene program (ANP, BNP, and βMHC) was also blunted in PMCA4 −/− TAC mice. Invasive hemodynamic and echocardiographic assessments revealed that WT-TAC animals displayed reduced contractility as well as enlargement of LV chamber dimension compared to PMCA4 −/− TAC mice as indicated by preload recruitable stroke work (PRSW) and LV end diastolic dimension (LVEDD) suggesting a protection from the development of LV dysfunction in PMCA4 −/− mice. We then analysed the molecular pathway which might be modified by PMCA4 gene ablation. While ERK1/2, JNK and GSK3β were not differently activated, we found that Akt activation was reduced in PMCA4 −/− TAC compared to WT-TAC, possibly via an NO dependent mechanism. Our results suggest that PMCA4 is a powerful regulator of myocardial hypertrophy and further strengthens the notion that PMCA4 is part of a novel signaling pathway in the myocardium. Table 1 Cardiac phenotype of PMCA4−/− mice after TAC or sham operation
Abstract 818: Modulation Of Catecholamine Secretion By In Vivo Gene Transfer Of G-protein Coupled Receptor Kinase (GRK) 2 Or A GRK2 Inhibitor Peptide In The Adrenal Gland
Authors: Giuseppe Rengo, Anastasios Lymperopoulos, Carmela Zincarelli, Stephen Soltys, Walter J Koch
Journal: Circulation (2007)

We recently reported that adrenal G-protein coupled Receptor Kinase (GRK) 2 up-regulation causes enhanced secretion of the catecholamines (CA‘s) epinephrine (Epi) and norepinephrine (NEpi) in chronic heart failure by desensitizing the α 2 -adrenergic receptors (ARs) of chromaffin cells (ChrCs), the autoreceptors responsible for autocrine feedback inhibition of CA release from these cells [ Lymperopoulos et al., Nat. Med. 2007 ; 13 : 315 –323 ]. In the present study, we sought to investigate whether modulation of adrenal GRK2 levels/activity regulates physiological CA secretion in vivo in rats. For this purpose, we devised two different in vivo adenoviral gene delivery methods to the adrenal medulla: direct injection in the suprarenal gland and retrograde delivery via the suprarenal veins, of GRK2 or of its inhibitor peptide βARKct, and we performed in vivo gene delivery in normal young Sprague-Dawley rats. We found that both delivery approaches are equally effective at inducing a robust (&gt;80% of the whole organ) and organ-restricted transgene expression in the whole adrenal gland, both in the cortical and medullary regions. Additionally, rats with AdenoGRK2 (AdGRK2)-infected adrenals exhibit enhanced plasma CA levels (235 ± 10 pg/ml for Epi, 333 ± 30 pg/ml for NEpi, n = 5) compared to control rats (adrenals injected with Adeno-Green Fluorescent Protein, AdGFP, or saline, 128 ± 6 pg/ml for Epi, 230 ± 10 pg/ml for NEpi, n = 5), whereas plasma CA levels in rats with AdβARKct-infected adrenals are significantly lower than control rats (30 ± 8 pg/ml for Epi, 67 ± 11 pg/ml for NEpi, n35). Finally, in ChrCs isolated from these infected adrenals, α 2 -AR stimulation with the specific α 2 -AR agonist UK14304 of AdGRK2-infected ChrCs failed to inhibit CA secretion in response to nicotine, which activates the nicotinic cholinergic receptors present in ChrCs, the physiological stimulus for CA secretion from these cells. In ChrCs derived from AdβARKct-infected adrenals in vivo however, the ability of UK14304 to inhibit nicotine-induced CA secretion was completely restored. These results suggest that adrenal GRK2 activity is a critical regulator of CA secretion in vivo, leading to increased CA secretion and plasma levels.
Abstract 2843: Significant Association between Neutrophil Aggregation in Aspirated Thrombus and Myocardial Damage in Patients with ST-segment Elevation Acute Myocardial Infarction
Authors: Kentaro Arakawa, Satoshi Yasuda, Hiroyuki Hao, Yu Kataoka, Isao Morii, Yoichiro Kasahara, Atsushi Kawamura, Hatsue Ishibashi-Ueda, Shunichi Miyazaki
Journal: Circulation (2006)

Background : The previous flow cytometric study demonstrated that circulating neutrophil-platelet aggregate formation is useful in vivo marker for platelet activation ( Circulation. 2001 ; 104 : 1533 –37 ). However, in patients with acute myocardial infarction (AMI), the relationships between myocardial damage, platelet activation and platelet-neutrophil aggregation remains unclear. Thrombotic samples aspirated in the culprit lesions may provide intraluminal pathological information. Methods : We studied 107 patients with ST-segment elevation AMI (M/F:77/30, age:66±12 [mean±SD]years), in whom aspiration catheter was used during emergency percutaneous coronary intervention. Patients were divided into the following two groups according to the density of neutrophils in the aspirated samples: group L (n=53), ≤100 neutrophils/0.025mm 2 thrombus; group H (n=54), &gt;100 neutrophil/0.025mm 2 thrombus). Left ventricular ejection fraction (LVEF) was reassessed six months after the onset of AMI. Results : Neutrophil density in thrombus was not time-dependent. Impaired myocardial reperfusion, defined as myocardial blush grade of 0/1 and no ST-segment resolution (&lt;50% of initial value) was more frequently found in group H than in group L. Peak creatinine phosphokinase (CPK) level was higher and LVEF at six months after the onset was lower in group H than group L. Multivariate analysis showed that high neutrophil density in aspirated thrombus was an independent predictor of myocardial blush grade 0/1, no ST-segment resolution and LVEF at six months after the onset with odds ratio of 13.3, 8.72 and 5.09, respectively (P&lt;0.01). Conclusions : Platelet-neutrophil aggregates retrieved from ruptured plaque may be associated with impairment of coronary microcirculation and resultant myocardial necrosis/dysfunction. These findings indicate the clinical importance of the interaction between thrombosis and inflammation in pathogenesis of AMI.
Abstract 3640: Cardiac Atrophy in Women After 8 Weeks of Bed Rest Deconditioning
Authors: Todd A Dorfman, Tommy Tillery, Ronald M Peshock, Jeff Hastings, Suzanne M Schneider, Brandon R Macias, Alan R Hargens, Benjamin D Levine
Journal: Circulation (2006)

Background : Chronic exposure to microgravity by bed rest or spaceflight induces cardiac atrophy which leads to reduced standing stroke volume and orthostatic intolerance. However despite the fact that orthostatic intolerance appears worse in female astronauts as well as patient populations, most previous high resolution studies of cardiac morphology after microgravity were performed only in men. Since female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have less physiological cardiac atrophy after bed rest. Methods : Magnetic resonance imaging (MRI) was performed in 24 healthy young women (32.1± 4yr.) to measure LV and RV mass, volumes and morphology accurately before and after 60 days of −6° head down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (N=8) or 2 control groups consisting of a) exercise training using supine treadmill running within lower body negative pressure plus resistive training (N=8); or b) protein supplementation (N=8; 0.6g/kg increase in protein long chain amino acids). Results : After sedentary bed rest without nutritional protein supplementation, there were significant reductions in LV (2.2 ± 0.2 to 2.0 ± 0.2 g/kg, P=0.001) and RV masses (0.8 ± 0.1 to 0.6 ± 0.1 g/kg, P&lt;0.001), similar to what has been observed previously in men (8.0% Perhonen 2001 ; JAP 91 : 645 –653 ). In contrast, there were significant increases in LV (1.9 ± 0.4 to 2.3 ± 0.3 g/kg, P&lt;0.001) and RV masses (0.7 ± 0.1 to 0.8 ± 0.2 g/kg, P=0.002) in the exercise trained controls. Protein supplementation led to an intermediate phenotype with no change in LV or RV mass after bed rest. Conclusions : Cardiac atrophy occurs in women similar to men following sedentary long term HDT bed rest. However, exercise training and to a lesser extent protein supplementation prevent the cardiac atrophy associated with microgravity simulated by strict bed rest.
Abstract 163: Protein Phosphatase Type 1 Induces Depressed Cardiac Function Via Microtubule Network Densification
Authors: Guangmao Cheng, Anandakumar Shunmugavel, Thomas N Gallien, Anna A DePaoli-Roach, George Cooper
Journal: Circulation (2007)

Type 1 protein phosphatase (PP1), a major cardiac Ser/Thr protein phosphatase isotype, is hyperactivated in the failing heart. Activated PP1 may induce cardiac dysfunction, at least in part through effects on calcium metabolism. A second abnormality of the failing heart is increased density of the cardiocyte microtubule (MT) network, caused in part by increased binding of microtubule-associated protein 4 (MAP4) to MTs. This abnormality is known to cause contractile dysfunction via viscous loading in severe pressure overload cardiac hypertrophy and failure. Since increased PP1 activity could dephosphorylate MAP4, which enhances MAP4 affinity for microtubule and thus microtubule assembly and stability, our hypothesis is that active PP1 may be causally linked to depressed cardiac function via microtubule network densification. To test this idea, we used transgenic mice having cardiac-restricted overexpression of the catalytic subunit of PP1 ( Mol Cell Biol. 2002 ; 22 : 4124 –35 ), wherein myocardial PP1 activity is increased ~3-fold. In these mice, the polymerized fraction of cardiac αβ-tubulin heterodimers was 1.5-fold higher than in same-strain WT controls. Consistent with this, microtubule network density via confocal microscopy was substantially greater in transgenic versus WT cardiocytes. To determine the effects of active PP1 on cardiac MT stability, colchicine (0.5 mg/kg, i.p.) was given to the mice. At 4 hours, the polymerized αβ-tubulin heterodimer fraction was significantly increased in PP1 overexpressing cardiocytes. Thus, increased activity of PP1 appears to increase MAP4 microtubule affinity, which in turn generates a dense network of stabilized microtubules. This cytoskeletal abnormality, which inhibits cardiac contraction, represents a second potential mechanism for the deleterious effects of PP1 overactivity on the heart.
Abstract 2383: Evaluation of a Multigenic Model of Stroke Risk in a Prospective Study of Patients with type 2 Diabetes: Results from the Go-DARTS Study
Authors: Anna Silvia Proia, Colin N Palmer, Alexander S Doney, Charlotte Kimber, Andrew D Morris, Andrea Flex, Eleonora Gaetani, Paolo Pola, Roberto Pola
Journal: Circulation (2006)

Background Recently, in a case-control study, we showed that history of ischemic stroke is significantly associated with genetic profiles determined by the combination of single polymorphisms of gene encoding inflammatory molecules ( Flex et al., Stroke 2004 ; 35 : 2270 –5 ). Following this observation, we investigated the influence of this multigenic model on stroke susceptibility in a large population-based prospective study. Methods This is a prospective study of 2,147 individuals with type 2 diabetes. Patients were part of the Go-DARTS Study, which is a sub-population of the large prospective diabetes register known as the DARTS (Diabetes Audit Research in Tayside Scotland) study, a continuously expanding region-wide register of subjects with diabetes containing clinical data on over 97% of patients in the Tayside region of Scotland. The following inflammatory single nucleotide polymorphisms (SNPs) were investigated, using the Taqman-based allelic discrimination assay: IL-6 -174 G/C, MCP-1 A2518G, ICAM-1 E469K, E-selectin Ser128Arg, MMP-3 5A/6A. The end-point of the study was the occurrence of non-fatal or fatal stroke. The mean follow-up was 6.2 years. Results During the period of observation, 108 strokes occurred. When considered alone, none of the investigated gene variants increased the risk for stroke, although the ICAM-1 polymorphism demonstrated a significant association with stroke in smokers (HR 2.6, P=0.02). However, when polymorphisms were evaluated in association, the incidence of stroke increased progressively according to the number of SNPs concomitantly carried by a given individual, from 1.0% in subjects bearing no risk variations to 10.8% in subjects with four pro-inflammatory genotypes. Among these individuals, the risk of developing stroke over the follow-up period exhibited a 13-fold increase compare to that observed in subjects with no risk variations. Conclusions This a large prospective cohort study providing evidence that pro-inflammatory genetic profiles, determined by the concomitant presence of inflammation-associated gene polymorphisms, increase the risk of stroke. This model might be used as template to test the synergistic role of multiple gene variations in the development of cardiovascular diseases.
Abstract 1023: Proprotein Convertase Subtilisin Kexin type 9 is repressed by the Peroxisome Proliferator Activated Receptor alpha ligand fenofibric acid.
Authors: Philippe Costet, Sanae Kourimate, Thierry Pineau, Michel Krempf
Journal: Circulation (2006)

Familial autosomal dominant hypercholesterolemia is characterized by high levels of cholesterol associated to LDL (LDLc), secondary to mutations in the LDL receptor, its ligand the apolipoprotein B or the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9). PCSK9 is a natural inhibitor of the LDLr and its absence reduces the risk for cardiovascular disease and increases sensitivity to statins. We recently showed that PCSK9’s expression is upregulated by insulin and the Liver X Receptor ligand T0901317, via SREBP-1c, and that it is downregulated by fasting. Here we show that the SREBP-1c response element we isolated in PCSK9 proximal promoter is also a sterol responsive element and mediates a large part of the promoter’s activation by statins. The decrease observed in PCSK9 expression during fasting couldn’t be entirely attributed to variations in SREBPs. New investigations show that this down regulation also involves an active repression by PPARalpha. Indeed PCSK9 mRNA is 4 fold (p = 0.01) more abundant in wild type mice than in PPARalpha -/- mice, after a 24h-long fasting, although fed mice present similar mRNA and protein levels. In vitro, in human immortalized hepatocytes, the PPARalpha agonist fenofibric acid (250 μM) diminished PCSK9 mRNA content by 75% (p = 0.002), its protein content by 65 % (p = 0.006), and its autocatalytic activity by −30%, (p = 0.02), as reflected by the cleavage of a peptide corresponding to the autocatalytic cleavage site ( Naureckiene S. et al. 2003 Arch. Biochem. Biophys. 420 : 55 –67. ). Fenofibric acid also prevented the Liver X Receptor-mediated activation of PCSK9 by T0901317. Among several PPAR agonist (ciprofibrate, clofibrate, gemfibrozil), fenofibric acid was the most efficient in reducing PCSK9 autocatalytic activity. These results suggest that fenofibric acid, or the next generation of PPARalpha agonists, might constitute good repressors of PCSK9 in humans.
Abstract 3145: High-resolution, High Frame-rate Strain Imaging for Early Myocardial Infarction Detection
Authors: Jianwen Luo, Kana Fujikura, Iwao Matsunaga, Shunichi Homma, Elisa E Konofagou
Journal: Circulation (2006)

Background : Myocardial elastography ( Konofagou EE et al, Ultrasound Med. Biol. 2002 ; 28 : 475 –482 ) is a novel technique for noninvasively imaging regional myocardial function. Methods : In vivo experiments were performed in anesthetized, nine normal and seven post-infarction (one day post-LAD ligation) mice using a high-resolution (30 MHz) ultrasound system (Vevo 770, VisualSonics Inc.). Radio-frequency signals and the associated electrocardiogram (ECG) were simultaneously acquired. Using an ECG triggering technique, an ultrafast frame rate of 8000 frames/s was achieved that resulted in high-quality strain estimation. The strains during the entire cardiac cycle were imaged using an elastographic technique. Results : High-resolution strain images (elastograms) clearly depicted all cardiac events including left-ventricular (LV) contraction, LV relaxation, atrial contraction and isovolumic phase in both normal and infarcted mice. The strain images showed a mechanical contrast of up to 10 times (p = 0.02) between normal and infarcted myocardia. Preliminary statistical results from normal mice (n = 9; p = 0.01) and infarcted mice (n = 7; p = 0.02) showed the cumulative strains during systole were equal to 0.56 ± 0.13 and −0.04 ± 0.32, respectively (see Fig. 1 ). Conclusion : Myocardial elastography can provide strain information at both high temporal and spatial resolution, and is capable of accurately characterizing normal myocardial function as well as detecting and localizing early myocardial infarction in vivo.
Abstract 3144: Imaging Myocardial Heterogeneity Using Propagation of Pulsive Vibration for Patients with Old Myocardial Infarction
Authors: Hiroshi Kanai, Sachiko Watanabe, Yoshifumi Saijo, Motonao Tanaka
Journal: Circulation (2006)

Background: It is well known that the diseased area due to old myocardial infarction (OMI) becomes fibrous. This study shows that a novel method noninvasively visualizes myocardial heterogeneity for patients with OMI. Method: By a sparse sector scan, the myocardial minute motions were measured simultaneously at about 1,000 points in the heart wall at a high frame rate (&gt; 400 Hz). We have found that a pulsive vibration is excited by aortic-valve closure ( Ultrasound Med Biol 2001 ; 27 : 481 ). The consecutive spatial distributions of the vibrations clearly reveal that the vibration propagates from the root of the aortic valve to the apex along the heart wall ( IEEE Trans UFFC 2005 ; 51 : 1931 ). Since its propagation time along the heart wall and the duration period are only several milliseconds and its amplitude is about 100 μm, this phenomenon cannot be measured by conventional equipments. In this study, the method was applied to 7 healthy subjects and 5 patients with OMI, and the spatial distribution of the propagation speed of the vibration is also visualized. In Vivo Experiments: For all healthy subjects, the propagation of the pulsive vibration was clearly visible both in longitudinal-axis and apical views. Even for the healthy subjects, there is spatial difference in the propagation speed; 4.3 ± 0.5 m/s for the high echo area and 2.9 ± 0.4 m/s for the low echo area, for 60 Hz component in the septum. For all patients with OMI, in the normal region the vibration propagated, but it did not propagate in the diseased area as shown in the consecutive figures at every 4 ms. Conclusions: These preliminary results indicate that the method has a potential for noninvasively revealing myocardial heterogeneity .