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See detailPlasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain.
Mohamed, Tamer M. A.; Oceandy, Delvac; Zi, Min et al

in The Journal of biological chemistry (2011), 286(48), 41520-9

Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding of cardiac physiology and pathophysiology. Although there is growing evidence that ... [more ▼]

Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding of cardiac physiology and pathophysiology. Although there is growing evidence that the plasma membrane Ca(2+)/calmodulin-dependent ATPase 4 (PMCA4) is a regulator of neuronal nitric-oxide synthase, the physiological consequence of this regulation is unclear. We therefore tested the hypothesis that PMCA4 has a key structural role in tethering neuronal nitric-oxide synthase to a highly compartmentalized domain in the cardiac cell membrane. This structural role has functional consequences on cAMP and cGMP signaling in a PMCA4-governed microdomain, which ultimately regulates cardiac contractility. In vivo contractility and calcium amplitude were increased in PMCA4 knock-out animals (PMCA4(-/-)) with no change in diastolic relaxation or the rate of calcium decay, showing that PMCA4 has a function distinct from beat-to-beat calcium transport. Surprisingly, in PMCA4(-/-), over 36% of membrane-associated neuronal nitric-oxide synthase (nNOS) protein and activity was delocalized to the cytosol with no change in total nNOS protein, resulting in a significant decrease in microdomain cGMP, which in turn led to a significant elevation in local cAMP levels through a decrease in PDE2 activity (measured by FRET-based sensors). This resulted in increased L-type calcium channel activity and ryanodine receptor phosphorylation and hence increased contractility. In the heart, in addition to subsarcolemmal calcium transport, PMCA4 acts as a structural molecule that maintains the spatial and functional integrity of the nNOS signaling complex in a defined microdomain. This has profound consequences for the regulation of local cyclic nucleotide and hence cardiac beta-adrenergic signaling. [less ▲]

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See detailDrug eluting stents for the treatment of bare metal in-stent restenosis: long-term outcomes in real world practice.
Appleby, Clare E.; Khattar, Raj S.; Morgan, Kenneth et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2011), 6(6), 748-53

AIMS: Drug eluting stents (DES) have had a great impact in reducing in-stent restenosis (ISR) in de novo lesions. However, long-term data regarding effectiveness and safety of these stents in treating ... [more ▼]

AIMS: Drug eluting stents (DES) have had a great impact in reducing in-stent restenosis (ISR) in de novo lesions. However, long-term data regarding effectiveness and safety of these stents in treating bare metal stent (BMS) ISR are limited. We report long-term clinical outcomes in a cohort of patients with BMS-ISR treated with DES between April 2002 and December 2003 at our institution. METHODS AND RESULTS: Sixty-nine consecutive patients with significant BMS-ISR were treated with DES implantation. Sirolimus DES were used in 43 patients and paclitaxel DES in 26. All patients were followed up to determine the incidence of major adverse cardiac event (MACE) rates (all-cause death, myocardial infarction, or target vessel revascularisation [TVR]), angina class and the need for clinically driven angiography. The mean age of the cohort was 58.6 +/- 10.8 years; 68% were male, 33% were diabetic, 50% had hypertension, 78% were on statin therapy and 59% were current (19%) or previous (41%) smokers. The clinical presentation of ISR was with chronic stable angina in 54 patients, 12 had a non-ST elevation acute coronary syndrome and three presented with ST-elevation myocardial infarction. Multivessel stenting was performed in 21 patients and bifurcation stenting in seven patients. Over a mean follow period of 4.9 years, the first event MACE rate was 20% (17 events in 14 patients - eight deaths of which three were cardiac, two non-fatal myocardial infarctions and seven TVR). Excluding non-cardiac death, the adjusted MACE rate was 14.5% (12 events in 10 patients). At long-term follow-up, mean Canadian angina class decreased from 2.3 +/- 0.7 pre-procedure to 1.2 +/- 0.4, 65% of patients were angina free and 80% were free of MACE. No differences in long-term outcomes were observed between patients receiving paclitaxel and sirolimus DES. CONCLUSIONS: The use of DES for the treatment of BMS-ISR is safe and effective over a mean follow-up period of nearly five years. To our knowledge, this represents the longest follow-up data of real world patients treated in a single interventional centre. [less ▲]

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See detailA comparison of drug-eluting stents versus bare metal stents in saphenous vein graft PCI outcomes: a meta-analysis.
Mamas, Mamas A.; Foley, James; Nair, Satheesh et al

in Journal of interventional cardiology (2011), 24(2), 172-80

AIMS: Studies demonstrate that percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is associated with reduced revascularization and major adverse cardiac events (MACE) rates compared ... [more ▼]

AIMS: Studies demonstrate that percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is associated with reduced revascularization and major adverse cardiac events (MACE) rates compared to bare metal stents (BMS) in native coronary vessels. Optimal PCI treatment of saphenous vein graft (SVG) lesions remains unclear despite SVG procedures representing up to 10% of PCI cases. We therefore performed a meta-analysis to compare outcomes between BMS and DES in SVG PCI. METHODS AND RESULTS: A search (2004-2009) of MEDLINE and conference proceedings for all relevant studies comparing mortality and MACE outcomes in DES versus BMS in SVG PCI and meta-analysis of the data was performed. Twenty studies were identified from 2005 to 2009 enrolling a total of 5,296 patients. Meta-analysis revealed a decrease in mortality associated with DES use, odds ratio (OR) 0.68; 95% confidence interval (CI) 0.53-0.88; P = 0.004. Similarly, MACE (OR 0.64; 95% CI 0.51-0.82; P < 0.001), total lesion revascularization (OR 0.60; 95% CI 0.43-0.83; P = 0.002), and total vessel revascularization (OR 0.57; 95% CI 0.41-0.80; P = 0.001) were significantly decreased in the patients in which DES were used compared to BMS. This reduction in mortality and MACE events associated with DES use appears to be limited to registry studies and not randomized controlled studies. CONCLUSIONS: Our meta-analysis suggests DES use to be safe in SVG PCI and associated with reduced mortality and MACE rates with reductions in revascularization also observed. [less ▲]

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See detailLate outcomes of drug eluting and bare metal stents in saphenous vein graft percutaneous coronary intervention.
Nair, Satheesh; Fath-Ordoubadi, Farzin; Clarke, Bernard et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2011), 6(8), 985-91

AIMS: PCI with drug eluting stents (DES) has been shown to reduce restenosis and major adverse cardiac event (MACE) rates compared to bare metal stents (BMS) in native coronary vessels, although outcomes ... [more ▼]

AIMS: PCI with drug eluting stents (DES) has been shown to reduce restenosis and major adverse cardiac event (MACE) rates compared to bare metal stents (BMS) in native coronary vessels, although outcomes in saphenous vein graft (SVG) lesions are less clear. We retrospectively studied 388 consecutive patients admitted to our centre for SVG PCI to assess mortality and MACE outcomes (defined as composite endpoint of all-death, stroke, myocardial infarction, stent thrombosis and target lesion (TLR)/vessel (TVR) revascularisation) associated with BMS and DES use. METHODS AND RESULTS: Two hundred and nineteen (219) patients had BMS and 169 had DES (total 388 patients). Mean follow up was 41.9+/-23.5 months. No significant differences were observed in mortality (14.2% vs. 11.8%) or MACE (37.6% vs. 35.8%) between the BMS and DES groups at four years follow-up or at other intervening time points studied. Similarly, no differences in TVR/TLR rates were observed over a similar time period (19.8% vs. 21.6%). CONCLUSIONS: We have observed that DES and BMS use in SVG PCI have comparable mortality and MACE rates, and that in contrast to PCI in native coronary arteries, DES do not reduce revascularisation rates in our study cohort. [less ▲]

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See detailLocal signals with global impacts and clinical implications: lessons from the plasma membrane calcium pump (PMCA4).
Oceandy, Delvac; Mohamed, Tamer M. A.; Cartwright, Elizabeth J. et al

in Biochimica et biophysica acta (2011), 1813(5), 974-8

Calcium has been unequivocally regarded as a key signal messenger in almost every cell type. Calcium regulates a number of important cellular functions including cell growth, myofilament contraction, cell ... [more ▼]

Calcium has been unequivocally regarded as a key signal messenger in almost every cell type. Calcium regulates a number of important cellular functions including cell growth, myofilament contraction, cell survival and apoptosis as well as gene transcription. A complex regulatory mechanism of cellular calcium is needed to fine tune the precise calcium concentration in each subcellular location and also to transmit the signals carried by the calcium pool to the correct end target. In this article we will review the recently emerging role of the plasma membrane calcium/calmodulin dependent ATPase isoform 4 (PMCA4) in regulating calcium signalling. We will then focus on the function of this molecule in cardiomyocytes, in which PMCA4 forms protein-protein interactions with several key signalling molecules. Recent evidence has shown in vivo physiological functionalities and possible clinical implications of the PMCA4 signalling complex. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. [less ▲]

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See detailMitogen-activated protein kinase kinase 4 deficiency in cardiomyocytes causes connexin 43 reduction and couples hypertrophic signals to ventricular arrhythmogenesis.
Zi, Min; Kimura, Tomomi E.; Liu, Wei et al

in The Journal of biological chemistry (2011), 286(20), 17821-30

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See detailCalcium signaling dysfunction in heart disease.
Cartwright, Elizabeth J.; Mohamed, Tamer; Oceandy, Delvac et al

in BioFactors (Oxford, England) (2011), 37(3), 175-81

In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must ... [more ▼]

In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca(2+) concentrations during each contraction and relaxation cycle. This review highlights a number of proteins that regulate signaling Ca(2+) in both normal and pathological conditions including cardiac hypertrophy and heart failure, and discusses how these pathways are not regulated by the marked elevation in free intracellular calcium ([Ca(2+) ](i)) during contraction but require smaller sustained increases in Ca(2+) concentration. In addition, we present published evidence that the pool of Ca(2+) that regulates signaling is compartmentalized into distinct cellular microdomains and is thus distinct from that regulating contraction. [less ▲]

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See detailAutomated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets.
Brown, Marie; Wedge, David C.; Goodacre, Royston et al

in Bioinformatics (2011), 27(8), 1108-12

MOTIVATION: The study of metabolites (metabolomics) is increasingly being applied to investigate microbial, plant, environmental and mammalian systems. One of the limiting factors is that of chemically ... [more ▼]

MOTIVATION: The study of metabolites (metabolomics) is increasingly being applied to investigate microbial, plant, environmental and mammalian systems. One of the limiting factors is that of chemically identifying metabolites from mass spectrometric signals present in complex datasets. RESULTS: Three workflows have been developed to allow for the rapid, automated and high-throughput annotation and putative metabolite identification of electrospray LC-MS-derived metabolomic datasets. The collection of workflows are defined as PUTMEDID_LCMS and perform feature annotation, matching of accurate m/z to the accurate mass of neutral molecules and associated molecular formula and matching of the molecular formulae to a reference file of metabolites. The software is independent of the instrument and data pre-processing applied. The number of false positives is reduced by eliminating the inaccurate matching of many artifact, isotope, multiply charged and complex adduct peaks through complex interrogation of experimental data. AVAILABILITY: The workflows, standard operating procedure and further information are publicly available at http://www.mcisb.org/resources/putmedid.html. CONTACT: warwick.dunn@manchester.ac.uk. [less ▲]

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See detailThe role of metabolites and metabolomics in clinically applicable biomarkers of disease.
Mamas, Mamas; Dunn, Warwick B.; Neyses, Ludwig UL et al

in Archives of toxicology (2011), 85(1), 5-17

Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography ... [more ▼]

Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography coupled to mass spectrometry, typically in discovery phases of studies. Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes or pharmacologic responses to a therapeutic intervention. Biomarkers are widely used in clinical practice for the diagnosis, assessment of severity and response to therapy in a number of clinical disease states. In human studies, metabolomics has been applied to define biomarkers related to prognosis or diagnosis of a disease or drug toxicity/efficacy and in doing so hopes to provide greater pathophysiological understanding of disease or therapeutic toxicity/efficacy. This review discusses the application of metabolomics in the discovery and subsequent application of biomarkers in the diagnosis and management of inborn errors of metabolism, cardiovascular disease and cancer. We critically appraise how novel biomarkers discovered through metabolomic analysis may be utilized in future clinical practice by addressing the following three fundamental questions: (1) Can the clinician measure them? (2) Do they add new information? (3) Do they help the clinician to manage patients? Although a number of novel biomarkers have been discovered through metabolomic studies of human diseases in the last decade, none have currently made the transition to routine use in clinical practice. Metabolites identified from these early studies will need to form the basis of larger, prospective, externally validated studies in clinical cohorts for their future use as biomarkers. At this stage, the absolute quantification of these biomarkers will need to be assessed epidemiologically, as will the ultimate deployment in the clinic via routine biochemistry, dip stick or similar rapid at- or near-patient care technologies. [less ▲]

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See detailWhat influences physical activity in people with heart failure?: a qualitative study.
Tierney, Stephanie; Elwers, Heather; Sange, Chandbi et al

in International journal of nursing studies (2011), 48(10), 1234-43

BACKGROUND: Research has highlighted the benefits of physical activity for people with stable heart failure in improving morbidity and quality of life. However, adherence to exercise among this patient ... [more ▼]

BACKGROUND: Research has highlighted the benefits of physical activity for people with stable heart failure in improving morbidity and quality of life. However, adherence to exercise among this patient group is low. Barriers and enablers to sustained physical activity for individuals with heart failure have been little investigated. OBJECTIVES: To explore reasons why people with heart failure do and do not engage in regular physical activity. DESIGN: A qualitative, interview-based investigation. SETTINGS: Three heart failure clinics held at hospitals in the UK. PARTICIPANTS: Purposive sampling was adopted to provide maximum variation in terms of gender, age, heart failure duration and severity, and current activity levels. Twenty two patients (7=female) were interviewed, aged between 53 and 82 years. METHODS: Semi-structured interviews were conducted via telephone. These were recorded and transcribed verbatim. Framework analysis was applied to collected data. RESULTS: Interviewees' narratives suggested that adopting positive health behaviours was complex, affected by internal and external factors. This was reflected in the four themes identified during analysis: fluctuating health; mental outlook; others' expectations; environmental influences. Failure to exercise arose because of symptoms, co-morbidities, poor sense of self as active and/or lack of perceived benefit. Likewise, encouragement from others and inclement weather affected exercising. CONCLUSIONS: Areas identified during interviews as influencing activity levels relate to those commonly found in behavioural change theories, namely perceived costs and benefits, self-efficacy and social support. These are concepts that practitioners may consider when devising interventions to assist patients with heart failure in undertaking and maintaining regular exercise patterns. [less ▲]

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See detailDeprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload.
Liu, Wei; Zi, Min; Chi, Hongbo et al

in Journal of molecular and cellular cardiology (2011), 50(4), 702-11

There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein ... [more ▼]

There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein kinase kinase 7 (MKK7) is a critical component of stress-activated MAP kinase signaling pathway. The role of MKK7 plays in mediating cardiac remodeling in response to load stress has yet to be defined. Herein, we investigate the role of MKK7 in regulating cardiac remodeling in response to pressure overload. We generated and examined the phenotype of mice with cardiomyocyte-specific deletion of the mkk7 gene (MKK7(cko)). Following one week of pressure overload, MKK7(cko) mice exhibited characteristic phenotypes of heart failure evidenced by deterioration in ventricular function and pulmonary congestion. Cell death assays revealed an increased prevalence of cardiomyocyte apoptosis in the MKK7(cko) heart, in which elevated p53 levels and attenuated expression of manganese superoxide dismutase (MnSOD) were found. Moreover, extensive interstitial fibrosis was discovered in the knockout heart likely attributable to upregulation of transforming growth factor beta (TGF-beta) signaling. These results reveal an essential role of MKK7 in cardiomyocytes for protecting the heart from hypertrophic insults thereby preventing the transition to heart failure. [less ▲]

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See detailWhat can we learn from patients with heart failure about exercise adherence? A systematic review of qualitative papers.
Tierney, Stephanie; Mamas, Mamas; Skelton, Dawn et al

in Health psychology : official journal of the Division of Health Psychology, American Psychological Association (2011), 30(4), 401-10

OBJECTIVES: Keeping physically active has been shown to bring positive outcomes for patients diagnosed with heart failure (HF). However, a number of individuals with this health problem do not undertake ... [more ▼]

OBJECTIVES: Keeping physically active has been shown to bring positive outcomes for patients diagnosed with heart failure (HF). However, a number of individuals with this health problem do not undertake regular exercise. A review of extant qualitative research was conducted to explore what it can tell us about barriers and enablers to physical activity among people with HF. METHODS: A systematic search, involving electronic databases and endeavors to locate gray literature, was carried out to identify relevant qualitative studies published from 1980 onward. Data from retrieved papers were combined using framework analysis. Papers read in full numbered 32, and 20 were included in the review. RESULTS: Synthesis of results from the 20 studies resulted in 4 main themes: Changing soma, negative emotional response, adjusting to altered status, and interpersonal influences. How individuals responded to their diagnosis and their altered physical status related to their activity levels, as did the degree of encouragement to exercise coming from family, friends, and professionals. These findings can be connected to the theory of behavioral change developed by Bandura, known as social cognitive theory (SCT). CONCLUSIONS: SCT may be a useful framework for developing interventions to support patients with HF in undertaking and maintaining regular exercise patterns. Specific components of SCT that practitioners may wish to consider include self-efficacy and outcome expectancies. These were issues referred to in papers for the systematic review that appear to be particularly related to exercise adherence. [less ▲]

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See detailIntegration of metabolomics in heart disease and diabetes research: current achievements and future outlook.
Dunn, Warwick B.; Goodacre, Royston; Neyses, Ludwig UL et al

in Bioanalysis (2011), 3(19), 2205-22

Metabolomics is an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of mammalian systems through the study of endogenous and exogenous metabolites in cells ... [more ▼]

Metabolomics is an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of mammalian systems through the study of endogenous and exogenous metabolites in cells, tissues, culture supernatants as well as biofluids. In the last 5 years an increase in the number of metabolomic investigations of cardiovascular diseases and diabetes has been observed. In this article the experimental strategies applied and recent examples of their application in disease and drug efficacy/toxicity biomarker detection and the employment for the discovery of new molecular pathophysiological processes related to disease onset and progression, as well as their usefulness in drug efficacy/toxicity, will be reviewed. An outlook of the requirements for future successes will also be discussed. [less ▲]

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See detailUse of the sheathless guide catheter during routine transradial percutaneous coronary intervention: a feasibility study.
Mamas, Mamas; D'Souza, Savio; Hendry, Cara et al

in Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions (2010), 75(4), 596-602

OBJECTIVE: The aim of this study is to investigate the feasibility of using a 6.5 Fr sheathless guide catheter as a default system in transradial (TRA) percutaneous coronary intervention (PCI). BACKGROUND ... [more ▼]

OBJECTIVE: The aim of this study is to investigate the feasibility of using a 6.5 Fr sheathless guide catheter as a default system in transradial (TRA) percutaneous coronary intervention (PCI). BACKGROUND: TRA PCI has been shown to reduce mortality rates through a reduction in access site related bleeding complications compared with procedures performed though a femoral approach. Complications associated with the TRA route increase with the size of sheath used. These complications may be reduced by the use of a sheathless guide catheter system (Asahi Intecc, Japan) that is 1-2 Fr sizes smaller in diameter than the corresponding introducer sheath. METHODS: We performed PCI in 100 consecutive cases using 6.5 Fr sheathless guides to determine the procedural success, rates of symptomatic radial spasm and radial occlusion. RESULTS: Procedural success using the 6.5 Fr sheathless guide catheter system was 100% with no cases requiring conversion to a conventional guide and catheter system. There were no procedural complications recorded associated with the use of the catheter. Adjunctive devices used in this cohort included IVUS, stent delivery catheters, distal protection devices, and simple thrombectomy catheters. The rate of radial spasm was 5% and the rate of radial occlusion at 2 months was 2%. CONCLUSION: Use of the 6.5 Fr sheathless guide catheter system, which has an outer diameter <5 Fr sheath, as the default system in routine PCI is feasible with a high rate of procedural success via the radial artery. [less ▲]

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See detailEndothelial nitric oxide synthase activity is inhibited by the plasma membrane calcium ATPase in human endothelial cells.
Holton, Marylouisa; Mohamed, Tamer M. A.; Oceandy, Delvac et al

in Cardiovascular research (2010), 87(3), 440-8

AIMS: Nitric oxide (NO) plays a pivotal role in the regulation of cardiovascular physiology. Endothelial NO is mainly produced by the endothelial nitric oxide synthase (eNOS) enzyme. eNOS enzymatic ... [more ▼]

AIMS: Nitric oxide (NO) plays a pivotal role in the regulation of cardiovascular physiology. Endothelial NO is mainly produced by the endothelial nitric oxide synthase (eNOS) enzyme. eNOS enzymatic activity is regulated at several levels, including Ca(2+)/calmodulin binding and the interaction of eNOS with associated proteins. There is emerging evidence indicating a role for the plasma membrane calcium ATPase (PMCA) as a negative regulator of Ca(2+)/calmodulin-dependent signal transduction pathways via its interaction with partner proteins. The aim of our study was to investigate the possibility that the activity of eNOS is regulated through its association with endothelial PMCA. METHODS AND RESULTS: We show here a novel interaction between endogenous eNOS and PMCA in human primary endothelial cells. The interaction domains were located to the region 735-934 of eNOS and the catalytic domain of PMCA. Ectopic expression of PMCA in endothelial cells resulted in an increase in phosphorylation of the residue Thr-495 of endogenous eNOS. However, disruption of the PMCA-eNOS interaction by expression of the PMCA interaction domain significantly reversed the PMCA-mediated effect on eNOS phosphorylation. These results suggest that eNOS activity is negatively regulated via interaction with PMCA. Moreover, NO production by endothelial cells was significantly reduced by ectopic expression of PMCA. CONCLUSION: Our results show strong evidence for a novel functional interaction between endogenous PMCA and eNOS in endothelial cells, suggesting a role for endothelial PMCA as a negative modulator of eNOS activity, and, therefore, NO-dependent signal transduction pathways. [less ▲]

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See detailWhat are the thromboembolic risks of heart failure combined with chronic or paroxysmal AF?
Caldwell, Jane Cochrane; Mamas, Mamas A.; Neyses, Ludwig UL et al

in Journal of cardiac failure (2010), 16(4), 340-7

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common disorders that frequently occur together and are associated with an increased risk of thromboembolism. This thromboembolic risk may ... [more ▼]

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common disorders that frequently occur together and are associated with an increased risk of thromboembolism. This thromboembolic risk may be reduced by anticoagulation with warfarin but not without introducing new hemorrhagic risks. METHODS AND RESULTS: Current guidelines recommend the use of anticoagulation in patients with HF and chronic AF and paroxysmal AF (PAF) that is symptomatic or frequent and prolonged enough to be detected by electrocardiogram. However, the evidence supporting these recommendations is weak and does not take account of research indicating that the prothrombotic risk is higher in more severe HF. CONCLUSIONS: An area not addressed by current guidelines is anticoagulation in patients with HF and short, asymptomatic episodes of AF. These issues need to be resolved with further studies using implanted devices to detect such asymptomatic PAF. [less ▲]

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See detailA meta-analysis of glucose-insulin-potassium therapy for treatment of acute myocardial infarction.
Mamas, Mamas A.; Neyses, Ludwig UL; Fath-Ordoubadi, Farzin

in Experimental & Clinical Cardiology (2010), 15(2), 20-4

BACKGROUND: Glucose-insulin-potassium (GIK) therapy has been proposed to provide metabolic support to ischemic myocardium. A meta-analysis that included 1932 patients performed 10 years previously ... [more ▼]

BACKGROUND: Glucose-insulin-potassium (GIK) therapy has been proposed to provide metabolic support to ischemic myocardium. A meta-analysis that included 1932 patients performed 10 years previously demonstrated that GIK therapy may have an important role in reducing mortality after acute myocardial infarction (AMI). Since then, many larger randomized trials investigating the role of GIK in the setting of AMI have been published; hence, the present study repeats the previous meta-analysis performed by the current authors to include these trials. METHOD AND RESULTS: A systematic MEDLINE search for all randomized, placebo-controlled studies of GIK therapy in the setting of AMI was conducted and a meta-analysis of the mortality data was performed. A total of 16 randomized trials from 1966 to 2008 were identified, with 28,374 patients included in the current meta-analysis. There was a total of 1367 deaths (9.6%) in the GIK group, with 1351 deaths (9.6%) in the control group. Meta-analysis did not reveal any benefit from GIK treatment (OR 1.0; 95% CI 0.9 to 1.1; P=0.9). Subgroup analysis of patients given high-dose GIK and in patients in whom reperfusion was not obtained did not demonstrate a benefit from GIK therapy. CONCLUSION: A meta-analysis of 16 randomized trials that spanned 40 years and involved more than 28,000 patients did not reveal any mortality benefit for ST segment elevation AMI using GIK therapy when data from the modern thrombolysis/primary percutaneous coronary intervention era were included. [less ▲]

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See detailThe effects of adding torasemide to standard therapy on peak oxygen consumption, natriuretic peptides, and quality of life in patients with compensated left ventricular systolic dysfunction.
Gupta, Sanjay; Waywell, Carolyn; Gandhi, Nandkumar et al

in European journal of heart failure (2010), 12(7), 746-52

AIMS: Diuretics, when used to treat congestion in patients with chronic heart failure, improve symptoms and, perhaps, prognosis but little information is available to guide their use in patients with left ... [more ▼]

AIMS: Diuretics, when used to treat congestion in patients with chronic heart failure, improve symptoms and, perhaps, prognosis but little information is available to guide their use in patients with left ventricular systolic dysfunction (LVSD) who are not congested. Chronic diuretic therapy causes persistent and potentially harmful neuroendocrine activation. Alternatively, in patients in whom neuroendocrine activation is blocked with angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers, diuretics may be beneficial by decreasing preload and afterload and preventing congestion. We aimed to assess the effect of the loop diuretic, torasemide on quality of life, and surrogate markers of prognosis when given to patients with LVSD who were not clinically congested and who were optimally treated with ACE-inhibitors (or angiotensin receptor antagonists) and beta-blockers. METHODS AND RESULTS: Thirty patients with stable LVSD who had no clinically detectable fluid overload were randomized to receive either torasemide 5 mg daily or placebo for 3 months (Phase A), and after a washout phase of 2 months, cross-over was performed for 3 months (Phase B). Diuretic therapy did not cause significant change in peak VO(2), mean N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) levels, or measures of quality of life compared with placebo. Diuretic therapy did however lead to significant fall in systolic and diastolic blood pressures and increase in plasma renin levels compared with placebo. CONCLUSION: Diuretic therapy with torasemide is not superior to placebo in improving peak VO(2) or reducing NT-proBNP levels in patients with left ventricular dysfunction who are not clinically congested. [less ▲]

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See detailResting Pd/Pa measured with intracoronary pressure wire strongly predicts fractional flow reserve.
Mamas, Mamas A.; Horner, Simon; Welch, Elise et al

in The Journal of invasive cardiology (2010), 22(6), 260-5

OBJECTIVE: To investigate the relationship between resting distal coronary pressure to aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) obtained during maximal hyperemia. BACKGROUND: FFR is ... [more ▼]

OBJECTIVE: To investigate the relationship between resting distal coronary pressure to aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) obtained during maximal hyperemia. BACKGROUND: FFR is an invasive index of the functional severity of a coronary artery stenosis determined from coronary pressure measurements. It is generally believed that there is little correlation between resting Pd/Pa and FFR obtained during maximal hyperemia. We have therefore studied this relationship in a large cohort of patients who had undergone pressure- wire assessments. METHODS: 528 consecutive pressure-wire studies performed in 483 patients over a 2-year period were retrospectively analyzed. RESULTS: A linear correlation between resting Pd/Pa and FFR post-pharmacological hyperemia was observed (rho = 0.74; p < 0.0001). When a FFR of < or = 0.75 (or < or = 0.80 as per FAME) was defined as positive, a resting Pd/Pa of < or = 0.85 (< or = 0.87) had a positive predictive value (PPV) of 95% (94.6%), while a resting Pd/Pa of > or = 0.93 (> or = 0.96) had a negative predictive value (NPV) of 95.7% (93%). CONCLUSIONS: We demonstrate a strong correlation between resting Pd/Pa and FFR. Resting values of Pd/Pa can be used to predict a positive FFR result with relatively high PPV and NPV. This may potentially obviate the need for adenosine infusion in a proportion of pressure-wire studies. [less ▲]

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