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See detailInfluence of arterial access site selection on outcomes in primary percutaneous coronary intervention: are the results of randomized trials achievable in clinical practice?
Mamas, Mamas A.; Ratib, Karim; Routledge, Helen et al

in JACC. Cardiovascular interventions (2013), 6(7), 698-706

OBJECTIVES: This study sought to investigate the influence of access site utilization on mortality, major adverse cardiac and cardiovascular events (MACCE), bleeding, and vascular complications in a large ... [more ▼]

OBJECTIVES: This study sought to investigate the influence of access site utilization on mortality, major adverse cardiac and cardiovascular events (MACCE), bleeding, and vascular complications in a large number of patients treated by primary percutaneous coronary intervention (PPCI) in the United Kingdom over a 5-year period, through analysis of the British Cardiovascular Intervention Society database. BACKGROUND: Despite advances in antithrombotic and antiplatelet therapy, bleeding complications remain an important cause of morbidity and mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing PPCI. A significant proportion of such bleeding complications are related to the access site, and adoption of radial access may reduce these complications. These benefits have not previously been studied in a large unselected national population of PPCI patients. METHODS: Mortality (30-day), MACCE (a composite of 30-day mortality and in-hospital myocardial re-infarction, target vessel revascularization, and cerebrovascular events), and bleeding and access site complications were studied based on transfemoral access (TFA) and transradial access (TRA) site utilization in PPCI STEMI patients. The influence of access site selection was studied in 46,128 PPCI patients; TFA was used in 28,091 patients and TRA in 18,037. Data were adjusted for potential confounders using Cox regression that accounted for the propensity to undergo radial or femoral approach. RESULTS: TRA was independently associated with a lower 30-day mortality (hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.52 to 0.97; p < 0.05), in-hospital MACCE (HR: 0.73, 95% CI: 0.57 to 0.93; p < 0.05), major bleeding (HR: 0.37, 95% CI: 0.18 to 0.74; p < 0.01), and access site complications (HR: 0.38, 95% CI: 0.19 to 0.75; p < 0.01). CONCLUSIONS: This analysis of a large number of PPCI procedures demonstrates that utilization of TRA is independently associated with major reductions in mortality, MACCE, major bleeding, and vascular complication rates. [less ▲]

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See detailA novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin.
Liu, Wei; Zi, Min; Tsui, Hoyee et al

in Circulation. Heart failure (2013), 6(4), 833-44

BACKGROUND: Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence ... [more ▼]

BACKGROUND: Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence indicates that restraining hypertrophy could be beneficial; here, we discovered that FTY-720, an immunomodulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy/fibrosis. METHODS AND RESULTS: Male C57/Bl6 mice underwent transverse aortic constriction (TAC) for 1 week followed by FTY-720 treatment for 2 weeks under continuing TAC. Compared with vehicle-treated TAC hearts, FTY-720 significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance. Mechanistic studies led us to discover that FTY-720 appreciably inhibited nuclear factor of activated T-cells (NFAT) activity. Moreover, we found that in primary cardiomyocytes (rat and human) pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720. This observation was confirmed in a mouse model of pressure overload. Interestingly, gene array analysis of TAC hearts revealed that FTY-720 profoundly decreased gene expression of a group of matricellular proteins, of which periostin was prominent. Analysis of periostin protein expression in TAC-myocardium, as well as in rat and human cardiac fibroblasts, confirmed the array data. Moreover, we found that FTY-720 treatment or knockdown of periostin protein was able to inhibit transforming growth factor-beta responsiveness and decrease collagen expression. CONCLUSIONS: FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu. Together, FTY-720 or its analogues could be a promising new approach for treating hypertrophic/fibrotic heart disease. [less ▲]

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See detailActivation of sphingosine-1-phosphate signalling as a potential underlying mechanism of the pleiotropic effects of statin therapy.
Egom, Emmanuel E.; Rose, Robert A.; Neyses, Ludwig UL et al

in Critical reviews in clinical laboratory sciences (2013), 50(3), 79-89

The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed ... [more ▼]

The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease. Key points Several studies have demonstrated a benefit from lowering serum LDL-C with statins in patients with and without clinical evidence of CAD. These may be mediated by the pleiotropic effects of statins-the mechanisms of which are incompletely understood. Early evidence suggests that statins may increase S1P signalling pathways through upregulation of the expression of S1P receptors and an increase in plasma levels of S1P to ultimately exert their pleiotropic effects. Future clinical trials and basic science research aimed at the underlying mechanisms of the pleiotropic effects of statins should enlighten us to their relative clinical relevance and importance. [less ▲]

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See detailAtrial fibrillation in heart failure: The sword of Damocles revisited.
Khan, Muhammad A.; Ahmed, Fozia; Neyses, Ludwig UL et al

in World Journal of Cardiology (2013), 5(7), 215-27

Heart failure (HF) and atrial fibrillation (AF) frequently coexist and have emerged as major cardiovascular epidemics. There is growing evidence that AF is an independent prognostic marker in HF and ... [more ▼]

Heart failure (HF) and atrial fibrillation (AF) frequently coexist and have emerged as major cardiovascular epidemics. There is growing evidence that AF is an independent prognostic marker in HF and affects patients with both reduced as well as preserved LV systolic function. There has been a general move in clinical practice from a rhythm control to a rate control strategy in HF patients with AF, although recent data suggests that rhythm control strategies may provide better outcomes in selected subgroups of HF patients. Furthermore, various therapeutic modalities including pace and ablate strategies with cardiac resynchronisation or radiofrequency ablation have become increasingly adopted, although their role in the management of AF in patients with HF remains uncertain. This article presents an overview of the multidimensional impact of AF in patients with HF. Relevant literature is highlighted and the effect of various therapeutic modalities on prognosis is discussed. Finally, while novel anticoagulants usher in a new era in thromboprophylaxis, research continues in a variety of new pathways including selective atrial anti-arrhythmic agents and genomic polymorphisms in AF with HF. [less ▲]

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See detailOptimisation and validation of a high throughput screening compatible assay to identify inhibitors of the plasma membrane calcium ATPase pump--a novel therapeutic target for contraception and malaria.
Mohamed, Tamer M. A.; Zakeri, Simon A.; Baudoin, Florence et al

in Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques (2013), 16(2), 217-30

PURPOSE: ATPases, which constitute a major category of ion transporters in the human body, have a variety of significant biological and pathological roles. However, the lack of high throughput assays for ... [more ▼]

PURPOSE: ATPases, which constitute a major category of ion transporters in the human body, have a variety of significant biological and pathological roles. However, the lack of high throughput assays for ATPases has significantly limited drug discovery in this area. We have recently found that the genetic deletion of the ATP dependent calcium pump PMCA4 (plasma membrane calcium/calmodulin dependent ATPase, isoform 4) results in infertility in male mice due to a selective defect in sperm motility. In addition, recent discoveries in humans have indicated that a single nucleotide polymorphism (SNP) in the PMCA4 gene determines the susceptibility towards malaria plasmodium infection. Therefore, there is an urgent need to develop specific PMCA4 inhibitors. In the current study, we aim to optimise and validate a high throughput screening compatible assay using recombinantly expressed PMCA4 and the HTRF(R) Transcreener(R) ADP (TR-FRET) assay to screen a drug library. METHODS AND RESULTS: PMCA4 membrane microsomes were prepared from HEK293 cells overexpressing PMCA4. Western blot quantification revealed nearly nine-fold increased expression of PMCA4 compared to LacZ (control virus)-infected cells. Maximal PMCA4 microsomal activity was achieved in the TR-FRET assay with 15ng/mul microsomal concentration, 30-minute pre-incubation with compounds at 37 degrees C, and calcium buffering with 1mM EGTA providing 1muM free-calcium. Finally a dose-response curve for carboxyeosin (a non-specific PMCA inhibitor) under optimised conditions showed significant PMCA4 inhibition. Upon confirmation that the assay was suitable for high-throughput screening, we have screened the ChemBioNet small molecule library (~21,000 compounds) against the PMCA4 assay to identify those that are its apparent inhibitors. This screening yielded 1,494 primary hits. CONCLUSIONS: We have optimised the HTRF(R) Transcreener(R) ADP assay for high-throughput screening to identify PMCA4 inhibitors. The output of the screening campaign has provided preliminary chemical starting points that could be further developed to specific PMCA4 inhibitors for non-hormonal contraception or anti-malaria therapy. [less ▲]

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See detailDevelopment and characterization of a novel fluorescent indicator protein PMCA4-GCaMP2 in cardiomyocytes.
Mohamed, Tamer M. A.; Abou-Leisa, Riham; Baudoin, Florence et al

in Journal of molecular and cellular cardiology (2013), 63

Isoform 4 of the plasma membrane calcium/calmodulin dependent ATPase (PMCA4) has recently emerged as an important regulator of several key pathophysiological processes in the heart, such as contractility ... [more ▼]

Isoform 4 of the plasma membrane calcium/calmodulin dependent ATPase (PMCA4) has recently emerged as an important regulator of several key pathophysiological processes in the heart, such as contractility and hypertrophy. However, direct monitoring of PMCA4 activity and assessment of calcium dynamics in its vicinity in cardiomyocytes are difficult due to the lack of molecular tools. In this study, we developed novel calcium fluorescent indicators by fusing the GCaMP2 calcium sensor to the N-terminus of PMCA4 to generate the PMCA4-GCaMP2 fusion molecule. We also identified a novel specific inhibitor of PMCA4, which might be useful for studying the role of this molecule in cardiomyocytes and other cell types. Using an adenoviral system we successfully expressed PMCA4-GCaMP2 in both neonatal and adult rat cardiomyocytes. This fusion molecule was correctly targeted to the plasma membrane and co-localised with caveolin-3. It could monitor signal oscillations in electrically stimulated cardiomyocytes. The PMCA4-GCaMP2 generated a higher signal amplitude and faster signal decay rate compared to a mutant inactive PMCA4(mut)GCaMP2 fusion protein, in electrically stimulated neonatal and adult rat cardiomyocytes. A small molecule library screen enabled us to identify a novel selective inhibitor for PMCA4, which we found to reduce signal amplitude of PMCA4-GCaMP2 and prolong the time of signal decay (Tau) to a level comparable with the signal generated by PMCA4(mut)GCaMP2. In addition, PMCA4-GCaMP2 but not the mutant form produced an enhanced signal in response to beta-adrenergic stimulation. Together, the PMCA4-GCaMP2 and PMCA4(mut)GCaMP2 demonstrate calcium dynamics in the vicinity of the pump under active or inactive conditions, respectively. In summary, the PMCA4-GCaMP2 together with the novel specific inhibitor provides new means with which to monitor calcium dynamics in the vicinity of a calcium transporter in cardiomyocytes and may become a useful tool to further study the biological functions of PMCA4. In addition, similar approaches could be useful for studying the activity of other calcium transporters during excitation-contraction coupling in the heart. [less ▲]

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See detailBiomarker-guided therapies in heart failure: a forum for unified strategies.
Fiuzat, Mona; O'Connor, Christopher M.; Gueyffier, Francois et al

in Journal of cardiac failure (2013), 19(8), 592-9

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in ... [more ▼]

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and meta-analyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union. [less ▲]

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See detailInfluence of access site selection on PCI-related adverse events in patients with STEMI: meta-analysis of randomised controlled trials.
Mamas, Mamas A.; Ratib, Karim; Routledge, Helen et al

in Heart (British Cardiac Society) (2012), 98(4), 303-11

OBJECTIVE: A meta-analysis of all randomised controlled studies that compare outcomes of transradial versus the transfemoral route to better define best practice in patients with ST elevation myocardial ... [more ▼]

OBJECTIVE: A meta-analysis of all randomised controlled studies that compare outcomes of transradial versus the transfemoral route to better define best practice in patients with ST elevation myocardial infarction (STEMI). DESIGN: A Medline and Embase search was conducted using the search terms 'transradial,' 'radial', 'STEMI', 'myocardial' and 'infarction'. SETTING: Randomised controlled studies that compare outcomes of transradial versus the transfemoral route. PATIENTS: A total of nine studies were identified that consisted of 2977 patients with STEMI. Interventions Studies that compare outcomes of transradial versus the transfemoral route. MAIN OUTCOME MEASURES: The primary clinical outcomes of interest were (1) mortality; (2) major adverse cardiac events (MACE); (3) major bleeding and (4) access site complications. RESULTS: Transradial PCI was associated with a reduction in mortality (OR 0.53, 95% CI 0.33 to 0.84; p=0.008), MACE (OR 0.62, 95% CI 0.43 to 0.90; p=0.012), major bleeding events (OR 0.63, 95% CI 0.35-1.12; p=0.12) and access site complications (OR 0.30, 95% CI 0.19 to 0.48; p<0.0001) compared with procedures performed through the femoral route. CONCLUSIONS: This meta-analysis demonstrates a significant reduction in mortality, MACE and major access site complications associated with the transradial access site in STEMI. The meta-analysis supports the preferential use of radial access for STEMI PCI. [less ▲]

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See detailRivaroxaban in patients with a recent acute coronary syndrome.
Mega, Jessica L.; Braunwald, Eugene; Wiviott, Stephen D. et al

in The New England journal of medicine (2012), 366(1), 9-19

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose ... [more ▼]

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.). [less ▲]

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See detailAtrial fibrillation in heart failure: an innocent bystander?
Khan, M. A.; Neyses, Ludwig UL; Mamas, M. A.

in Current cardiology reviews (2012), 8(4), 273-80

Heart failure (HF) and atrial fibrillation (AF) frequently coexist and each complicates the course of the other. The purpose of this review is to analyse the prognostic impact of AF in patients with HF ... [more ▼]

Heart failure (HF) and atrial fibrillation (AF) frequently coexist and each complicates the course of the other. The purpose of this review is to analyse the prognostic impact of AF in patients with HF and assess whether there is an advantage in targeting therapies towards the maintenance of sinus rhythm (SR) in this cohort of patients. The presence of AF in patients with HF has been reported to be independently associated with an increase in mortality in many studies and this increased risk is observed in those with both preserved and impaired LV systolic function. The optimal strategy for targeting AF in patients with HF is unclear but recent randomised controlled studies indicate no significant prognostic advantage associated with a rhythm control strategy as compared to a rate control strategy. A number of small studies have investigated the role of both cardiac resynchronization therapy (CRT) and AF catheter ablation for the maintenance of / conversion to SR in patients with HF with initial promising results although larger randomised controlled studies will need to be performed to define the role of these modalities in the treatment of this cohort and whether preliminary benefits observed in these studies translate to improvements in longer term prognosis. Finally, there has been a focus on modifying the arrhythmogenic atrial substrate and neurohormonal milieu by pharmacological means in order to prevent AF although it remains to be seen whether this approach proves to be efficacious with improvements in clinically relevant outcomes. [less ▲]

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See detailThe German Centre for Cardiovascular Research.
Prendergast, Bernard; Coope, Leslie T.; Crijns, Harry et al

in European heart journal (2012), 33(9), 1033-361036

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See detailUse of the Sideguard (Cappella) stent in bifurcation lesions: a real-world experience.
Mamas, Mamas A.; Farooq, Vasim; Latib, Azeem et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2012), 7(10), 1170-80

AIMS: The Sideguard(R) stent (Cappella Medical Devices Ltd, Galway, Ireland), is a novel nitinol self-expanding dedicated bifurcation stent that flares proximally at the ostium of the side branch (SB ... [more ▼]

AIMS: The Sideguard(R) stent (Cappella Medical Devices Ltd, Galway, Ireland), is a novel nitinol self-expanding dedicated bifurcation stent that flares proximally at the ostium of the side branch (SB) into a trumpet shape thereby achieving full ostial coverage. The aim of this study is to report the utility and limitations of this stent in patients undergoing treatment to bifurcation coronary lesions in a real-world setting. METHODS AND RESULTS: We prospectively identified 20 successive patients admitted over a 6-month period in whom there was significant SB disease and who were suitable for a bifurcation procedure. The Sideguard(R) stent was successfully used in all 20 cases including several that would have been technically difficult using conventional bifurcation techniques. We highlight use of this system using five illustrative cases that illustrate its utility and limitations in the treatment of bifurcation lesions. CONCLUSIONS: The Sideguard(R) stent can be used to treat complex bifurcation lesions in a straight forward manner and is not subject to the limitations associated with conventional bifurcation PCI techniques including jailing of the SB ostium and inability to fully cover/scaffold the ostium of the SB. [less ▲]

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See detailCardiac metabolism; from bench to bedside: Diabetic cardiomyopathy, a disease of cardiac metabolism?
Neyses, Ludwig UL

in Schilling, Joel D.; Mann, Douglas L. (Eds.) Diabetic cardiomyopathy: bench to bedside. (2012)

The study of diabetic cardiomyopathy is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical ... [more ▼]

The study of diabetic cardiomyopathy is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical definition and pathogenesis of this metabolic cardiomyopathy. This article reviews the current understanding of diabetic cardiomyopathy with a particular emphasis on the unresolved issues that have limited translation of scientific discovery to patient bedside. [less ▲]

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See detailWhat strategies are effective for exercise adherence in heart failure? A systematic review of controlled studies.
Tierney, Stephanie; Mamas, Mamas; Woods, Stephen et al

in Heart failure reviews (2012), 17(1), 107-15

Physical activity is recommended for people with stable heart failure (HF), because it is known to improve quality of life and health outcomes. However, adherence to this recommendation has been poor in ... [more ▼]

Physical activity is recommended for people with stable heart failure (HF), because it is known to improve quality of life and health outcomes. However, adherence to this recommendation has been poor in many studies. A systematic review was conducted to examine the effectiveness of strategies used to promote exercise adherence in those with HF. The following databases were searched for relevant literature published between January 1980 and December 2010: British Nursing Index; CINAHL; Cochrane Library; Embase; Medline and PsycINFO. Papers with a control group focused on adults with HF that measured exercise or physical activity adherence were included. Nine randomised controlled trials were identified, involving a total of 3,231 patients (range 16-2,331). Six of these studies were informed by specific psychological theories. Positive outcomes occurred in the short-term from interventions using approaches such as exercise prescriptions, goal setting, feedback and problem-solving. However, longer-term maintenance of exercise was less successful. There was some support for interventions underpinned by theoretical frameworks, but more research is required to make clearer recommendations. Addressing self-efficacy in relation to exercise may be a particularly useful area to consider in this respect. [less ▲]

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See detailRole of advanced glycation end products in cardiovascular disease.
Hegab, Zeinab; Gibbons, Stephen; Neyses, Ludwig UL et al

in World journal of cardiology (2012), 4(4), 90-102

Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions ... [more ▼]

Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF. [less ▲]

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See detailDisruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells.
Baggott, Rhiannon R.; Mohamed, Tamer M. A.; Oceandy, Delvac et al

in Carcinogenesis (2012), 33(12), 2362-8

Cancer is caused by defects in the signalling mechanisms that govern cell proliferation and apoptosis. It is well known that calcium-dependent signalling pathways play a critical role in cell regulation ... [more ▼]

Cancer is caused by defects in the signalling mechanisms that govern cell proliferation and apoptosis. It is well known that calcium-dependent signalling pathways play a critical role in cell regulation. A tight control of calcium homeostasis by transporters and channel proteins is required to assure a proper functioning of the calcium-sensitive signal transduction pathways that regulate cell growth and apoptosis. The plasma membrane calcium ATPase 2 (PMCA2) has been recently identified as a negative regulator of apoptosis that can play a significant role in cancer progression by conferring cells resistance to apoptosis. We have previously reported an inhibitory interaction between PMCA2 and the calcium-activated signalling molecule calcineurin in breast cancer cells. Here, we demonstrate that disruption of the PMCA2/calcineurin interaction in a variety of human breast cancer cells results in activation of the calcineurin/NFAT pathway, upregulation in the expression of the pro-apoptotic protein Fas Ligand and in a concomitant loss of cell viability. Reduction in cell viability is the consequence of an increase in cell apoptosis. Impairment of the PMCA2/calcineurin interaction enhances paclitaxel-mediated cytotoxicity of breast tumoral cells. Our results suggest that therapeutic modulation of the PMCA2/calcineurin interaction might have important clinical applications to improve current treatments for breast cancer patients. [less ▲]

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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 detailThe effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.
Cleland, John G. F.; Teerlink, John R.; Senior, Roxy et al

in Lancet (2011), 378(9792), 676-83

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are ... [more ▼]

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate (up to 2.7 beats per min; p<0.0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0.0026) and end-diastolic volumes (16 mL, p=0.0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc. [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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