A Flying Platform to Investigate Neuronal Correlates of Navigation in the Honey Bee (Apis mellifera).

Navigating animals combine multiple perceptual faculties, learn during exploration, retrieve multi-facetted memory contents, and exhibit goal-directedness as an expression of their current needs and motivations. Navigation in insects has been linked to a variety of underlying strategies such as path integration, view familiarity, visual beaconing, and goal-directed orientation with respect to previously learned ground structures. Most works, however, study navigation either from a field perspective, analyzing purely behavioral observations, or combine computational models with neurophysiological evidence obtained from lab experiments. The honey bee (Apis mellifera) has long been a popular model in the search for neural correlates of complex behaviors and exhibits extraordinary navigational capabilities. However, the neural basis for bee navigation has not yet been explored under natural conditions. Here, we propose a novel methodology to record from the brain of a copter-mounted honey bee. This way, the animal experiences natural multimodal sensory inputs in a natural environment that is familiar to her. We have developed a miniaturized electrophysiology recording system which is able to record spikes in the presence of time-varying electric noise from the copter's motors and rotors, and devised an experimental procedure to record from mushroom body extrinsic neurons (MBENs). We analyze the resulting electrophysiological data combined with a reconstruction of the animal's visual perception and find that the neural activity of MBENs is linked to sharp turns, possibly related to the relative motion of visual features. This method is a significant technological step toward recording brain activity of navigating honey bees under natural conditions. By providing all system specifications in an online repository, we hope to close a methodological gap and stimulate further research informing future computational models of insect navigation.

Fluid status telemedicine alerts for heart failure: a randomized controlled trial.

AIMS: Hospital admissions are frequently preceded by increased pulmonary congestion in heart failure (HF) patients. This study evaluated whether early automated fluid status alert notification via telemedicine improves outcome in HF patients. METHODS AND RESULTS: Patients recently implanted with an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy were eligible if one of three conditions was met: prior HF hospitalization, recent diuretic treatment, or recent brain natriuretic peptide increase. Eligible patients were randomized (1:1) to have fluid status alerts automatically transmitted as inaudible text message alerts to the responsible physician or to receive standard care (no alerts). In the intervention arm, following a telemedicine alert, a protocol-specified algorithm with remote review of device data and telephone contact was prescribed to assess symptoms and initiate treatment. The primary endpoint was a composite of all-cause death and cardiovascular hospitalization. We followed 1002 patients for an average of 1.9 years. The primary endpoint occurred in 227 patients (45.0%) in the intervention arm and 239 patients (48.1%) in the control arm [hazard ratio, HR, 0.87; 95% confidence interval (CI), 0.72-1.04; P = 0.13]. There were 59 (11.7%) deaths in the intervention arm and 63 (12.7%) in the control arm (HR, 0.89; 95% CI, 0.62-1.28; P = 0.52). Twenty-four per cent of alerts were not transmitted and 30% were followed by a medical intervention. CONCLUSION: Among ICD patients with advanced HF, fluid status telemedicine alerts did not significantly improve outcomes. Adherence to treatment protocols by physicians and patients might be challenge for further developments in the telemedicine field.

Five-year results of the Multicenter Randomized Controlled Open-Label Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients with De Novo Native Coronary Artery Lesions (SCORPIUS) study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic patients.

BACKGROUND: Because a delayed arterial healing response after drug-eluting stent implantation has raised concerns about safety in diabetic patients, long-term effects of treatment with sirolimus-eluting stent (SES), as compared with bare-metal stent (BMS), have to be established. The aim of the 5-year follow-up of the randomized, controlled, open-label multicenter SCORPIUS study was to assess long-term safety and efficacy of the CYPHER (Cordis, Johnson & Johnson, Bridgewater, NJ) SES in percutaneous coronary intervention of diabetic patients. METHODS: A total of 190 patients with type 2 diabetes mellitus were randomized to receive either a SES (n = 95) or a BMS (n = 95). Dual-antiplatelet therapy (aspirin plus clopidogrel) was prescribed for at least 6 months. Clinical follow-up data were scheduled at 1, 8, and 12 months and 5 years. RESULTS: Treatment with SES resulted in a 16% decrease in the rate of major adverse cardiac events (36% vs 52%; hazard ratio 0.6, 95% CI 0.4-0.9; P = .02). This reduction in major adverse cardiac events with SES at 5 years was mostly attributable to a lower number of repeat target lesion revascularization (13% vs 29%; hazard ratio 0.4, 95% CI 0.2-0.7; P = .003). No differences between groups were observed for safety end points (all-cause mortality 21% vs 21%, cardiac death 15% vs 13%, repeat myocardial infarction 8% vs 9%, and stent thrombosis 5% vs 6%) at 5 years. CONCLUSIONS: The 5-year follow-up of the SCORPIUS trial demonstrates the long-term antirestenotic efficacy of SES in diabetic patients with significantly reduced target lesion revascularization and comparable rates of mortality, myocardial infarction, and stent thrombosis compared with BMS.

Sustained risk of recurrent thromboembolic events in patients with patent foramen ovale and paradoxical embolism: long-term follow-up over more than 15 years.

BACKGROUND: Patients with patent foramen ovale (PFO) and cryptogenic stroke are at risk of recurrence. Therapeutic regimens range from no treatment to anticoagulation treatment to surgical or interventional closure. However, long-term follow-up is only available for up to 4 years. METHODS: Among ~5,000 transesophageal echocardiographies in stroke/TIA-patients between 1988 and 1997, a PFO was found and considered a possible mediator for the neurological event in 97 patients. In these patients, the PFO was judged to be responsible for the neurological event. Patients with cardiac or other reasons for embolism were excluded. The therapy for stroke was chosen by the attending physician. Follow-up information was obtained through telephone interviews. RESULTS: Follow-up was available for 86 patients (89%) with a mean period of 15.4 years (range, 11.2-25.9 years). Thirteen patients (15%) suffered from recurrent ischemic events (7 TIAs, 5 strokes, 1 peripheral embolism) after a mean period of 4.9 years. Four patients died, not associated with recurrent thromboembolism. The risk of recurrence was increased over the entire length of the mean follow-up period. The occurrence of recurrent events was not associated with differences in baseline data, the presence of ASA, PFO size or the chosen treatment. CONCLUSION: In patients with paradoxical embolism, recurrent ischemic events are frequent despite medical therapy. These events are not limited to the early years after the index event; this long-term follow-up revealed a risk of occurrence over the entire follow-up. These patients have a sustained risk of recurrence, requiring lifetime protection, which should be considered in tailoring individual therapeutic strategies.

Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies.

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.

Fluid status monitoring with a wireless network to reduce cardiovascular-related hospitalizations and mortality in heart failure: rationale and design of the OptiLink HF Study (Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink).

AIMS: The Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink (OptiLink HF) study is designed to investigate whether OptiVol fluid status monitoring with an automatically generated wireless CareAlert notification via the CareLink Network can reduce all-cause death and cardiovascular hospitalizations in an HF population, compared with standard clinical assessment. Methods Patients with newly implanted or replacement cardioverter-defibrillator devices with or without cardiac resynchronization therapy, who have chronic HF in New York Heart Association class II or III and a left ventricular ejection fraction ≤35% will be eligible to participate. Following device implantation, patients are randomized to either OptiVol fluid status monitoring through CareAlert notification or regular care (OptiLink 'on' vs. 'off'). The primary endpoint is a composite of all-cause death or cardiovascular hospitalization. It is estimated that 1000 patients will be required to demonstrate superiority of the intervention group to reduce the primary outcome by 30% with 80% power. CONCLUSION: The OptiLink HF study is designed to investigate whether early detection of congestion reduces mortality and cardiovascular hospitalization in patients with chronic HF. The study is expected to close recruitment in September 2012 and to report first results in May 2014.

Exercise training improves in vivo endothelial repair capacity of early endothelial progenitor cells in subjects with metabolic syndrome.

BACKGROUND: Endothelial dysfunction and injury are considered to contribute considerably to the development and progression of atherosclerosis. It has been suggested that intense exercise training can increase the number and angiogenic properties of early endothelial progenitor cells (EPCs). However, whether exercise training stimulates the capacity of early EPCs to promote repair of endothelial damage and potential underlying mechanisms remain to be determined. The present study was designed to evaluate the effects of moderate exercise training on in vivo endothelial repair capacity of early EPCs, and their nitric oxide and superoxide production as characterized by electron spin resonance spectroscopy analysis in subjects with metabolic syndrome. METHODS AND RESULTS: Twenty-four subjects with metabolic syndrome were randomized to an 8 weeks exercise training or a control group. Superoxide production and nitric oxide (NO) availability of early EPCs were characterized by using electron spin resonance (ESR) spectroscopy analysis. In vivo endothelial repair capacity of EPCs was examined by transplantation into nude mice with defined carotid endothelial injury. Endothelium-dependent, flow-mediated vasodilation was analysed using high-resolution ultrasound. Importantly, exercise training resulted in a substantially improved in vivo endothelial repair capacity of early EPCs (24.0 vs 12.7%; p < 0.05) and improved endothelium-dependent vasodilation. Nitric oxide production of EPCs was substantially increased after exercise training, but not in the control group. Moreover, exercise training reduced superoxide production of EPCs, which was not observed in the control group. CONCLUSIONS: The present study suggests for the first time that moderate exercise training increases nitric oxide production of early endothelial progenitor cells and reduces their superoxide production. Importantly, this is associated with a marked beneficial effect on the in vivo endothelial repair capacity of early EPCs in subjects with metabolic syndrome.

Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional ß1-blockade.

OBJECTIVES: The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its ß1-receptor-blocking properties. BACKGROUND: Nebivolol is a third-generation selective ß1-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. METHODS: Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. RESULTS: Infarct size was similar among the groups. Both ß1-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. CONCLUSIONS: Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional ß1-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI.

Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction.

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling.

Understanding the transcriptional regulation of angiogenesis could lead to the identification of novel therapeutic targets. We showed here that the transcription factor GATA6 is expressed in different human primary endothelial cells as well as in vascular endothelial cells of mice in vivo. Activation of endothelial cells was associated with GATA6 nuclear translocation, chromatin binding, and enhanced GATA6-dependent transcriptional activation. siRNA-mediated down-regulation of GATA6 after growth factor stimulation led to a dramatically reduced capacity of macro- and microvascular endothelial cells to proliferate, migrate, or form capillary-like structures on Matrigel. Adenoviral overexpression of GATA6 in turn enhanced angiogenic function, especially in cardiac endothelial microvascular cells. Furthermore, GATA6 protected endothelial cells from undergoing apoptosis during growth factor deprivation. Mechanistically, down-regulation of GATA6 in endothelial cells led to increased expression of transforming growth factor (TGF) ß1 and TGFß2, whereas enhanced GATA6 expression, accordingly, suppressed Tgfb1 promoter activity. High TGFß1/ß2 expression in GATA6-depleted endothelial cells increased the activation of the activin receptor-like kinase 5 (ALK5) and SMAD2, and suppression of this signaling axis by TGFß neutralizing antibody or ALK5 inhibition restored angiogenic function and survival in endothelial cells with reduced GATA6 expression. Together, these findings indicate that GATA6 plays a crucial role for endothelial cell function and survival, at least in part, by suppressing autocrine TGFß expression and ALK5-dependent signaling.

Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical embolism: procedural and follow-up results after implantation of the Amplatzer®-occluder device.

BACKGROUND: Prevalence of patent foramen ovale (PFO) with detectable right-to-left shunt is higher in young adults with transient ischemic attack (TIA) and stroke compared to the general population. So far, published series included different occluder systems, various indications and regimens of postprocedural anticoagulation. In our experience, occluder systems may be associated with an increased prevalence of thrombus formation, which has also reported by other groups. The aim of the present study was to evaluate the follow-up results after implantation of the Amplatzer® occluder in patients with PFO using a consistent anticoagulation regimen. METHODS AND RESULTS: One-hundred and fourteen patients with PFO (60 men; age: 47 ± 13 years) and ≥1 thromboembolic event were included. Other causes for embolism were excluded. PFO-closure was successful in all patients. All patients were treated with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 6 months. TEE was repeated at a mean of 10.3 months. Mean clinical follow-up period was 18 ± 9 months. After a mean of 10 months, no patient had either a significant residual shunt nor a suspected thrombus formation on the occluder. During follow-up, 5 patients suffered from neurological events (1 stroke, 2 TIAs, 2 epileptic seizures), though complete closure of the PFO was documented by TEE. One patient suffered from bleeding complications (upper GI-bleeding). CONCLUSION: Percutaneous closure of PFO in symptomatic patients by Amplatzer® occluder represents an effective therapy with a low incidence of peri-interventional complications and recurrent thromboembolism. Thrombus formations on the occluder system were not detected in this cohort.

Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes.

AIMS: Mice with a cardiomyocyte (CM)-restricted knockout of signal transducer and activator of transcription 3 (STAT3-KO) develop spontaneous heart failure. We investigated the impact of STAT3-mediated regulation of microRNAs for pathophysiological alterations in the heart. METHODS AND RESULTS: MicroRNAchip and qRT-PCR analysis revealed elevated cardiac expression of miR-199a in STAT3-KO mice. Lentiviral shRNA-mediated STAT3-knock-down in neonatal rat CMs markedly increased miR-199a promoter activity and miR-199a levels indicative of a suppressive effect of STAT3 on miR-199a transcription. Up-regulated miR-199a in CM by pre-miR-199a transfection (pre-miR-199a-CM) reduced expression of components of the ubiquitin-proteasome system (UPS), i.e. the ubiquitin-conjugating enzymes Ube2g1 (mRNA and protein) and Ube2i (protein). Pre-miR-199a-CM or CM with siRNA-mediated down-regulation of Ube2i and Ube2g1 (siRNA-Ube2i/2g1-CM) displayed massive down-regulation of α- and ß-myosin heavy chain expression associated with disrupted sarcomere structures. In addition, protein arginine methyltransferase I (PRMT-I) expression and asymmetric dimethylarginine (ADMA) synthesis were increased in pre-miR-199a-CM or in siRNA-Ube2i/2g1-CM. Increased ADMA in cell culture supernatant (SN) from pre-miR-199a-CM or siRNA-Ube2i/2g1-CM lowered nitric oxide (NO) bioavailability of rat cardiac endothelial cells while lowering ADMA concentration in CM SNs by the PRMT inhibitor arginine methyltransferase inhibitor 1 (AMI-1) (100 µM) improved NO bioavailability. In STAT3-KO hearts Ube2i and Ube2g1 expression were markedly reduced. Human terminal failing hearts harbouring low STAT3 protein levels displayed increased miR-199a levels and decreased Ube2g1 expression. CONCLUSION: This study identifies a novel pathophysiological circuit in the heart between reduced STAT3 protein levels, increased miR-199a expression, and subsequent impairment of the UPS that disrupts CM sarcomere structure and impairs via the release of ADMA endothelial cell function.

Two vascular arteriovenous malformations with left-to-right shunting and right-heart failure in a single patient.

Arteriovenous malformations may lead to right-heart failure in cases of hemodynamically significant left-to-right shunting. Here, we report the case of a 37-year-old female who presented with congestive heart failure related to an isolated anomalous connection of the left pulmonary vein to the left brachiocephalic vein (partial anomalous pulmonary venous connection). After successful reconnection to the left appendage and clinical improvement, the patient once again developed progressive signs of heart failure. Several arteriovenous malformations were identified in the liver as the underlying cause of the patient's high-output heart failure, and the patient was retrospectively diagnosed with hereditary hemorrhagic telangiectasia. Target embolization led to right-ventricular remodeling, and persistent clinical improvement. To our knowledge, this is the first report of two rare AV-malformations with left-to-right shunting and progressive right-heart failure in a single individual.

Relation of diastolic and systolic function, exercise capacity and brain natriuretic peptide in adults after Mustard procedure for transposition of the great arteries.

OBJECTIVES: To evaluate the relation of echocardiographic parameters of diastolic function, exercise capacity (expressed as peakVO(2)) and NT-proBNP in patients with transposition of the great arteries (TGA) and Mustard procedure. METHODS: Diastolic function was determined by measuring tricuspid flow velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). E/Ea ratios were calculated. For assessment of systolic function, CMR was applied. RESULTS: E/A (r = 0.07, p = 0.66), E/Ea medial (r = 0.03, p = 0.84), E/Ea lateral (r = -0.01, p = 0.92), IVRT (r = -0.13, p = 0.44), and DT (r = -0.05, p = 0.76) were not correlated with peakVO(2). NT-proBNP showed a significant correlation with IVRT (r = 0.44, p = 0.004) and Ea/Aa medial (r = -0.34, p = 0.025). No correlation was found between RV systolic function and peakVO(2) (r = 0.07, p = 0.63). CONCLUSIONS: Exercise capacity in patients with TGA and Mustard procedure is not related to echocardiographic parameters of diastolic function. NT-proBNP is associated with selected echocardiographic parameters of diastolic function.

Chemokine receptor 7 knockout attenuates atherosclerotic plaque development.

BACKGROUND: Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice. METHODS AND RESULTS: CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7(-/-) T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7(-/-)-derived T cells primed with oxidized low-density lipoprotein-pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7(-/-)/ldlr(-/-) mice. CONCLUSION: These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.

Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. METHODS AND RESULTS: The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P=0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (P=0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. CONCLUSIONS: GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.

Usefulness of biomarker strategy to improve GRACE score's prediction performance in patients with non-ST-segment elevation acute coronary syndrome and low event rates.

We sought to assess whether multiple biomarkers would correlate with the outcome and could improve event prediction in non-ST-segment elevation acute coronary syndrome populations with low event rates. Nine inflammatory, ischemic, or neurohormonal biomarkers were measured within 48 hours after symptom onset in 440 patients with non-ST-segment elevation acute coronary syndrome from the ARCHIPELAGO (Irbesartan in Patients With Acute Coronary Syndrome Without ST Segment Elevation) trial. We assessed the relation between biomarkers and ischemic or heart failure composite end points at 2 months of follow-up. We also evaluated whether biomarkers could improve the predictive performance of the validated and well-performing Global Registry of Acute Coronary Events risk score. Among all biomarkers measured at baseline, only interleukin-6 correlated with the ischemic end point (adjusted odds ratio 1.69, 95% confidence interval [CI] 1.23 to 2.31). The independent correlates of the heart failure end point were B-type natriuretic peptide (adjusted odds ratio 3.16, 95% CI 1.99 to 5.03), aldosterone (adjusted odds ratio 1.57, 95% CI 1.14 to 2.16) and matrix metalloproteinase-9 (adjusted odds ratio 0.64, 95% CI 0.46 to 0.88). The Global Registry of Acute Coronary Events score predicted poorly the ischemic end point (area under the curve [AUC] 0.591) and fairly (AUC 0.775) the heart failure end point. The performance of the models was significantly improved by the introduction of interleukin-6 (AUC 0.685) for the ischemic end point and of the 3 biomarkers (AUC 0.874) for the heart failure end point. In conclusion, the interleukin-6 level only, and B-type natriuretic peptide, aldosterone, and matrix metalloproteinase-9 together, independently correlated with the ischemic and heart failure end points, respectively. The Global Registry of Acute Coronary Events risk score's performance was significantly improved with a biomarker strategy. In low-risk populations, a strategy using these biomarkers might help in identifying patients at greater risk of additional events.

CIB1 is a regulator of pathological cardiac hypertrophy.

Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain-containing protein Ca(2+) and integrin-binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain-containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca(2+) channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin-nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, beta isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.

Diagnostic accuracy of handheld echocardiography for evaluation of aortic stenosis.

BACKGROUND: Symptomatic severe aortic stenosis is associated with increased mortality and morbidity. Early identification of these patients by echocardiography is crucial. We conducted this study to evaluate a handheld ultrasound device (HCU) in patients with suspected severe aortic stenosis (AS) in comparison to a standard echocardiography device (SE). METHODS: A HCU (Vivid I; GE Healthcare) and a SE device (Philips iE 33) were used to evaluate 50 consecutive patients with suspected severe AS. Two consecutive echocardiographic studies were performed by two experienced and blinded examiners using HCU and SE device. AS was graded by mean transaortic pressure, aortic valve area (AVA), and indexed AVA (AVA adjusted for body surface area). RESULTS: Mean difference for mean transaortic gradient, AVA and indexed AVA for the SE and HCU device were 1.28 mmHg (-0.70 to 3.26 mmHg), -0.02 cm(2) (-0.06 to 0.01 cm(2)), and -0.01 cm(2)/m(2) (-0.03 to 0.01 cm(2)/m(2)), respectively. Discrepancies between both devices were not associated with misinterpretation of the degree of AS. CONCLUSION: Our study demonstrates that HCU can be used to evaluate patients with suspected AS. (ECHOCARDIOGRAPHY 2010;27:481-486).

Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction.

BACKGROUND: In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. METHODS AND RESULTS: The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) [Y(757)F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y(757)F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y(757)F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. CONCLUSIONS: Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.