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See detailTargeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart.
Kimura, Tomomi E.; Jin, Jiawei; Zi, Min et al

in Circulation Research (2010), 106(5), 961-70

RATIONALE: Mitogen-activated protein kinase (MAPK) pathways provide a critical connection between extrinsic and intrinsic signals to cardiac hypertrophy. Extracellular signal-regulated protein kinase (ERK ... [more ▼]

RATIONALE: Mitogen-activated protein kinase (MAPK) pathways provide a critical connection between extrinsic and intrinsic signals to cardiac hypertrophy. Extracellular signal-regulated protein kinase (ERK)5, an atypical MAPK is activated in the heart by pressure overload. However, the role of ERK5 plays in regulating hypertrophic growth and hypertrophy-induced apoptosis is not completely understood. OBJECTIVE: Herein, we investigate the in vivo role and signaling mechanism whereby ERK5 regulates cardiac hypertrophy and hypertrophy-induced apoptosis. METHODS AND RESULTS: We generated and examined the phenotypes of mice with cardiomyocyte-specific deletion of the erk5 gene (ERK5(cko)). In response to hypertrophic stress, ERK5(cko) mice developed less hypertrophic growth and fibrosis than controls. However, increased apoptosis together with upregulated expression levels of p53 and Bad were observed in the mutant hearts. Consistently, we found that silencing ERK5 expression or specific inhibition of its kinase activity using BIX02189 in neonatal rat cardiomyocytes (NRCMs) reduced myocyte enhancer factor (MEF)2 transcriptional activity and blunted hypertrophic responses. Furthermore, the inhibition of MEF2 activity in NRCMs using a non-DNA binding mutant form of MEF2 was found to attenuate the ERK5-regulated hypertrophic response. CONCLUSIONS: These results reveal an important function of ERK5 in cardiac hypertrophic remodeling and cardiomyocyte survival. The role of ERK5 in hypertrophic remodeling is likely to be mediated via the regulation of MEF2 activity. [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 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 detailPlasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways.
Holton, Mary Louisa; Wang, Weiguang; Emerson, Michael et al

in World Journal of Biological Chemistry (2010), 1(6), 201-8

Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs ... [more ▼]

Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular free calcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulin-dependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways. [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 and 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 detailImpaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated?
Mamas, Mamas A.; Deaton, Christi; Rutter, Martin K. et al

in Journal of cardiac failure (2010), 16(9), 761-8

BACKGROUND: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin ... [more ▼]

BACKGROUND: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear. METHODS AND RESULTS: The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR. CONCLUSIONS: We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients. [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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See detailThe cardiovascular phenotype of a mouse model of acromegaly.
Izzard, Ashley S.; Emerson, Michael; Prehar, Sukhpal et al

in Growth Hormone and IGF Research (2009), 19(5), 413-9

BACKGROUND: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy ... [more ▼]

BACKGROUND: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy or is a consequence of atherosclerosis secondary to the metabolic syndrome often observed in this condition. Direct comparison of a mouse model of acromegaly to a mouse model of Laron's syndrome allowed us to carry out detailed phenotyping and better understand the role GH plays in the circulatory system. METHODS AND RESULTS: Transgenic mice that overexpress the growth hormone gene (GH) developed gigantism, including insulin resistance and higher blood pressures commensurate with increased body mass. In these giant mice, the hearts were hypertrophied but haemodynamic studies suggested contractile function was normal. Segments of small arteries mounted in a pressure myograph showed vascular wall hypertrophy but a preserved lumen diameter. Vascular contractile function was normal. Mice in which the GH receptor gene was disrupted or 'knocked out' were dwarf and had low blood pressure, small hearts and blood vessels but a normally functioning circulation. Correlations of body mass with cardiovascular parameters suggested that blood pressure and structural characteristics develop in line with body size. CONCLUSION: In this transgenic mouse model of acromegaly, there is cardiac and vascular hypertrophy commensurate with GH excess but normal function. Our findings support the contention that the excess mortality in this condition may be due to the development of hypertrophic cardiomyopathy rather than increased rates of atherosclerotic coronary artery disease. [less ▲]

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See detailTumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy.
Oceandy, Delvac; Pickard, Adam; Prehar, Sukhpal et al

in Circulation (2009), 120(7), 607-16

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan ... [more ▼]

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy. METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras. CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway. [less ▲]

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See detailRas-association domain family member 1A (RASSF1A)-where the heart and cancer meet.
Oceandy, Delvac; Cartwright, Elizabeth J.; Neyses, Ludwig UL

in Trends in cardiovascular medicine (2009), 19(8), 262-7

The close relationship between signaling pathways regulating tumor growth and cardiac hypertrophy has attracted considerable interest. Although the involvement of proto-oncogenes in positively modulating ... [more ▼]

The close relationship between signaling pathways regulating tumor growth and cardiac hypertrophy has attracted considerable interest. Although the involvement of proto-oncogenes in positively modulating myocardial hypertrophy has long been recognized, little is known about factors that counterregulate them. In this article, we review the novel tumor suppressor Ras-association domain family protein isoform 1A (RASSF1A), which strongly inhibits the prohypertrophic Ras-Raf1-ERK1/2 pathway in the heart. RASSF1A interacts with a number of important signaling molecules regulating cell growth, survival, and apoptosis; therefore, it serves as a key adaptor molecule that integrates the upstream stimuli and transduces them to the selective downstream effectors. [less ▲]

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See detailCardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.
Liu, Wei; Zi, Min; Jin, Jiawei et al

in Circulation Research (2009), 104(7), 905-14

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen ... [more ▼]

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of mkk4 (MKK4(cko) mice). In response to pressure overload or chronic beta-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4(cko) mice. However, when subjected to swimming exercise, MKK4(cko) mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4(f/f)). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway. [less ▲]

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See detailAtrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy.
Caldwell, Jane C.; Contractor, Hussain; Petkar, Sanjiv et al

in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (2009), 11(10), 1295-300

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic heart failure (CHF). Under-detection of asymptomatic paroxysmal AF (PAF) underestimates the true burden of ... [more ▼]

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic heart failure (CHF). Under-detection of asymptomatic paroxysmal AF (PAF) underestimates the true burden of AF in patients with CHF. We retrospectively studied the prevalence of asymptomatic PAF in 162 CHF patients through analysis of cardiac resynchronization therapy (CRT) device downloads to determine whether these episodes are associated with adverse outcomes. METHODS AND RESULTS: An episode of AF was defined by mode switching on CRT devices with an atrial rate >200 for at least 30 s. Of the 101 patients thought to be persistently in sinus rhythm (SR), 27% were found to have significant paroxysms of AF, with the cumulative percentage of time in the 'mode-switch mode' (i.e. the AF burden) of 1.6 +/- 0.9%. Mortality was 19.2% in patients with newly identified PAF with hospitalization and thrombo-embolism rates of 42.3 and 2.1%, respectively, compared with mortality of 10.4% with hospitalization and thrombo-embolism rates of 41.8 and 1.9%, respectively, in patients persistently in SR (P= NS). CONCLUSION: Analysis of data from CRT devices in a population of CHF patients with severe left ventricular dysfunction shows that a significant proportion of those perceived to be persistently in SR have undiagnosed paroxysms of AF but with relatively low burden. These episodes appear to be associated with a trend towards increased mortality but no effects on hospitalization or thrombo-embolism rates. [less ▲]

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See detailSpecific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium.
Mohamed, Tamer M. A.; Oceandy, Delvac; Prehar, Sukhpal et al

in The Journal of biological chemistry (2009), 284(18), 12091-8

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds ... [more ▼]

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart and that this complex regulates beta-adrenergic signal transmission in vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG) showed a significant reduction in nNOS and total NOS activities as well as in cGMP levels in the heart compared with their wild type (WT) littermates. In contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a 3-fold increase in Ser(16) phospholamban (PLB) phosphorylation as well as Ser(22) and Ser(23) cardiac troponin I (cTnI) phosphorylation at base line compared with the WT. In addition, the relative induction of PLB phosphorylation and cTnI phosphorylation following isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining the blunted physiological response to the beta-adrenergic stimulation. In keeping with the data from the transgenic animals, neonatal rat cardiomyocytes overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP levels. This was accompanied by an increase in cAMP levels, which led to an increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP levels were likely due to the modulation of cardiac phosphodiesterase, which determined the balance between cGMP and cAMP following PMCA4b overexpression. In conclusion, these results showed that the nNOS-PMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI. [less ▲]

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See detailEstrogen receptor alpha interacts with 17beta-hydroxysteroid dehydrogenase type 10 in mitochondria.
Jazbutyte, Virginija; Kehl, Franz; Neyses, Ludwig UL et al

in Biochemical and biophysical research communications (2009), 384(4), 450-4

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human ... [more ▼]

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human heart cDNA library to detect novel protein-protein interaction partners of ERalpha in the heart. 17beta-Hydroxysteroid dehydrogenase type 10 (17beta-HSD10), which converts potent (17beta-estradiol) to less potent estrogens (estrone), co-localized with 17beta-HSD10 in the mitochondria of rat cardiac myocytes. GST pull-down experiments confirmed the interaction of ERalpha and 17beta-HSD10. These findings suggest that the ERalpha estrogen receptor might be involved in regulating intracellular estrogen levels by modulating 17beta-HSD10 activity. [less ▲]

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See detailPhysiological implications of the interaction between the plasma membrane calcium pump and nNOS.
Cartwright, Elizabeth J.; Oceandy, Delvac; Neyses, Ludwig UL

in Pflügers Archiv: European Journal of Physiology (2009), 457(3), 665-71

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in ... [more ▼]

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in intracellular-free calcium, has been associated with numerous diseases. One of the several transporters involved in calcium homeostasis is a P-type ATPase known as the plasma membrane calcium/calmodulin-dependent ATPase (PMCA) which is involved in calcium extrusion from the cytosol to the extracellular compartment. It has long been established that in many cell types, in particular non-excitable cells, the primary role of PMCA is in the bulk transport of intracellular calcium; however, its role in excitable cells is less clear. In the heart, for example, calcium is essential for contractile function as well as being a key messenger in signal transduction pathways; however, the mechanisms by which the cardiomyocyte distinguishes between these roles of calcium remain unclear. It is perhaps the transporters not involved in the contractile cycle (such as PMCA) that are able to carry non-contractile signals. This review will highlight the role of PMCA as a modulator of signal transduction pathways and in particular the role of isoform 4 in the regulation of the nitric oxide signalling pathway. [less ▲]

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See detailUse of the Heartrail II catheter as a distal stent delivery device; an extended case series.
Mamas, Mamas A.; Eichhofer, Jonas; Hendry, Cara et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2009), 5(2), 265-71

AIMS: The Terumo Heartrail catheter (Terumo Corp., Tokyo, Japan) allows extra deep catheter intubation of coronary vessels and has been shown to be useful in CTO lesions. The aim of this study is to ... [more ▼]

AIMS: The Terumo Heartrail catheter (Terumo Corp., Tokyo, Japan) allows extra deep catheter intubation of coronary vessels and has been shown to be useful in CTO lesions. The aim of this study is to assess the safety and efficacy of using the Heartrail II catheter as a distal stent delivery system in PCI following failure of conventional techniques. METHODS AND RESULTS: We prospectively identified cases performed over a 15-month period in which a Heartrail catheter was used to facilitate stent delivery following failure of conventional techniques. Stent delivery using the Heartrail catheter was performed in 35 cases and was successful in 31 cases. Success rates of 100% in grafts, 95% in RCA, 80% in LAD and 60% in circumflex cases were recorded respectively. Successful stent delivery was associated with intubation depth, with 29/29 succeeding when the intubation depth was > 2 cm and failure in 4/5 cases when the intubation depth <or= 2 cm. There were no complications related to deep intubation of the catheter. CONCLUSIONS: Use of the Heartrail catheter is safe and highly effective for aiding stent delivery across proximal obstructions in both left and right coronary systems. The small number of unsuccessful cases were related to inability of the catheter to traverse stenotic proximal obstructions within 2 cm of the RCA and LCA origins. [less ▲]

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See detailA meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure.
Mamas, Mamas A.; Caldwell, Jane C.; Chacko, Sanoj et al

in European journal of heart failure (2009), 11(7), 676-83

AIMS: Atrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have ... [more ▼]

AIMS: Atrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have therefore performed this meta-analysis to study the effects of the presence of AF on mortality in CHF patients. METHODS AND RESULTS: A systematic MEDLINE search for all randomized trials and observational studies in which the influence of AF on CHF mortality was investigated and meta-analysis of the mortality data was performed. A total of 16 studies were identified of which 7 were randomized trials and 9 were observational studies including 30,248 and 23,721 patients, respectively. An adjusted meta-analysis of the data revealed that the presence of AF is associated with an adverse effect on total mortality with an odds ratio (OR) of 1.40 [95% confidence interval (CI) 1.32-1.48, P < 0.0001] in randomized trials and an OR of 1.14 (95% CI 1.03-1.26, P < 0.05) in observational studies. This increase in mortality associated with the presence of AF was observed in subgroups of CHF patients with both preserved and impaired left ventricular (LV) systolic function. CONCLUSION: In conclusion, meta-analysis of 16 studies involving 53,969 patients suggests that the presence of AF is associated with an adverse prognosis in CHF irrespective of LV systolic function. [less ▲]

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See detailCardiovascular manifestations associated with influenza virus infection.
Mamas, Mamas Andreas; Fraser, Doug; Neyses, Ludwig UL

in International journal of cardiology (2008), 130(3), 304-9

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on ... [more ▼]

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. Epidemiological studies have demonstrated an association between influenza epidemics and cardiovascular mortality and a decrease in cardiovascular mortality in high risk patients has been demonstrated following vaccination with influenza vaccine. Influenza is a recognised cause of myocarditis which can lead to significant impairment of cardiac function and mortality. With recent concerns regarding another potential global pandemic of influenza the huge potential for cardiovascular morbidity and mortality is discussed. [less ▲]

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See detailExtensive catheter-induced aortic dissection.
Mamas, M. A.; Alonso, A.; Neyses, Ludwig UL

in The Canadian journal of cardiology (2008), 24(2), 9-10

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See detailHow common is asymptomatic paroxysmal atrial fibrillation in chronic heart failure?
Caldwell, Jane; Mamas, Mamas; Garratt, Clifford et al

in Scandinavian Cardiovascular Journal (2008), 42(6), 366367

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