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See detailAngiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
Packer, Milton; McMurray, John J. V.; Desai, Akshay S. et al

in Circulation (2015), 131(1), 54-61

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the ... [more ▼]

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. [less ▲]

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See detailPatients with cardiovascular risk factors were more likely to have lower life satisfaction.
Baumann, Michèle UL; Tchicaya, Anastase

in Circulation (2015), 132

Five years after coronary angiography, life satisfaction (LS) among patients may be related to incidents of cardiovascular diseases, risk factors and unhealthy behaviours and socioeconomic conditions but ... [more ▼]

Five years after coronary angiography, life satisfaction (LS) among patients may be related to incidents of cardiovascular diseases, risk factors and unhealthy behaviours and socioeconomic conditions but their respective influence remains unclear. Our aim is to analyze LS and its relationships with those factors. Methods. Among the 4,391 patients initially contacted, 547 deaths were reported and 209 had an invalid address. 3,635 patients who underwent coronary angiography in 2008-2009 at the National Institute of Cardiac Surgery and Cardiological Intervention (INCCI) in Luxembourg completed a self-questionnaire assessing LS [1-10] and other covariates. Data were analysed via multiple regression models adjusted initially on age, sex and income, and for a second time with the addition of all CVRF. Results. LS of 1,289 volunteers (69.2 years) was 7.3/10. Most were men, Luxembourgish, employees and manual workers, had secondary education and an income of 36,000 euros or more per year. LS was lowest in female patients, those with a low to middle income. Patients who live in couple had the best LS. Patients with a history in the previous 5 years of physical inactivity (regression coefficient: – 0.903), angina pectoris (rc -0.843), obesity (rc -0.512), diabetes, or hypercholesterolemia, were more likely to have lower LS. The previous associations were mostly maintained on the second analysis, with the exceptions of diabetes and obesity. In addition, patients who stopped smoking because of peer pressure (rc -0.011) had a lower LS. Conclusions. Profiles of patients are linked with least LS: ‘inclined abstainers’ who intended to modify their behaviours, but could not do it, and ‘disinclined abstainers’ who had no intention of changing and were insufficiently concerned to do so. Patients who stopped smoking and perceived it as unpleasant also had the lowest LS. ‘Declined actors’ were those patients who had to adjust their lifestyles, but were ambivalent about their intentions and the behaviour, which they continued. Health promotion programs would benefit from targeting factors that moderate the unfavourable intention-behaviour relationship and can help enhance LS. [less ▲]

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See detailPak1 as a novel therapeutic target for antihypertrophic treatment in the heart.
Liu, Wei; Zi, Min; Naumann, Ronald et al

in Circulation (2011), 124(24), 2702-15

BACKGROUND: Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to ... [more ▼]

BACKGROUND: Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy. METHODS AND RESULTS: Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1(cko)). When subjected to 2 weeks of pressure overload, Pak1(cko) mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1(cko) mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1(cko) mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation. CONCLUSIONS: These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure. [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 detailA change of scene: Ludwig Neyses, MD. Interview by Mark Nicholls.
Neyses, Ludwig UL; Neyes, Ludwig

in Circulation (2007), 116(3), 13-5

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See detailNeuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.
Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael et al

in Circulation (2007), 115(4), 483-92

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the ... [more ▼]

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the isoform 4b of plasma membrane calcium/calmodulin-dependent ATPase (PMCA4b) through direct interaction mediated by a PDZ domain (PSD 95, Drosophilia Discs large protein and Zona occludens-1) on nNOS and a cognate ligand on PMCA4b. It remains unknown, however, whether this interaction has physiological relevance in the heart in vivo. METHODS AND RESULTS: We generated 2 strains of transgenic mice overexpressing either human PMCA4b or PMCA ct120 in the heart. PMCA ct120 is a highly active mutant form of the pump that does not interact with or modulate nNOS function. Calcium was extruded normally from PMCA4b-overexpressing cardiomyocytes, but in vivo, overexpression of PMCA4b reduced the beta-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (N omega-propyl-L-arginine) reduced the beta-adrenergic response in wild-type and ct120 transgenic mice to levels comparable to those of PMCA4b transgenic animals. No differences in lusitropic response were observed in either transgenic strain compared with wild-type littermates. CONCLUSIONS: These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart. [less ▲]

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See detailIncreased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction.
Pelzer, Theo; Loza, Paula-Anahi Arias; Hu, Kai et al

in Circulation (2005), 111(12), 1492-8

BACKGROUND: Lower mortality rates among women with chronic heart failure than among men may depend in part on the action of female sex hormones, especially estrogens. The biological effects of estrogens ... [more ▼]

BACKGROUND: Lower mortality rates among women with chronic heart failure than among men may depend in part on the action of female sex hormones, especially estrogens. The biological effects of estrogens are mediated by 2 distinct estrogen receptor (ER) subtypes (ERalpha and ERbeta). The present study was undertaken to determine the role of ERbeta in the development of chronic heart failure after experimental myocardial infarction (MI). METHODS AND RESULTS: Female ERbeta null mice (BERKO(Chapel Hill)) and wild-type littermates (WT) were ovariectomized, given 17beta-estradiol, and subjected to chronic anterior MI (MI; BERKO n=31, WT n=30) or sham operation (sham; BERKO n=14, WT n=14). At 8 weeks after MI, both genotypes revealed left ventricular remodeling and impaired contractile function at similar average infarct size (BERKO-MI 32.9+/-5% versus WT-MI 33.0+/-4%); however, BERKO mice showed increased mortality (BERKO-MI 42% versus WT-MI 23%), increased body weight and fluid retention (P<0.01), higher ventricular pro-ANP expression (BERKO-MI 27.9-fold versus sham, WT-MI 5.2-fold versus sham; BERKO-MI versus WT-MI P<0.001), higher atrial natriuretic peptide serum levels, and increased phospholamban expression (P<0.05) compared with WT mice. CONCLUSIONS: Systemic deletion of ERbeta in female mice increases mortality, aggravates clinical and biochemical markers of heart failure, and contributes to impaired expression of Ca(2+)-handling proteins in chronic heart failure after MI. Further studies are required to delineate the relative importance of cardiac and vascular effects of ERbeta and the role of ERalpha in the development of heart failure. [less ▲]

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See detailTargeted proteolysis sustains calcineurin activation.
Burkard, Natalie; Becher, Jan; Heindl, Cornelia et al

in Circulation (2005), 111(8), 1045-53

BACKGROUND: Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload ... [more ▼]

BACKGROUND: Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload leads to increased CnA activity in human myocardium. Here, we investigated the proteolytic mechanism leading to activation of CnA. METHODS AND RESULTS: In patients with diseased myocardium, we found strong nuclear translocation of CnA. In contrast, in normal human myocardium, there was a cytosolic distribution of CnA. Stimulation of rat cardiomyocytes with angiotensin (Ang) II increased calpain activity significantly (433+/-11%; P<0.01; n=6) and caused proteolysis of the autoinhibitory domain of CnA. Inhibition of calpain by a membrane-permeable calpain inhibitor prevented proteolysis. We identified the cleavage site of calpain in the human CnA sequence at amino acid 424. CnA activity was increased after Ang II stimulation (310+/-29%; P<0.01; n=6) and remained high after removal of Ang II (214+/-17%; P<0.01; n=6). Addition of a calpain inhibitor to the medium decreased CnA activity (110+/-19%; P=NS; n=6) after removal of Ang II. Ang II stimulation of cardiomyocytes also translocated CnA into the nucleus as demonstrated by immunohistochemical staining and transfection assays with GFP-tagged CnA. Calpain inhibition and therefore suppression of calpain-mediated proteolysis of CnA enabled CnA exit from the nucleus. CONCLUSIONS: Ang II stimulation of cardiomyocytes increased calpain activity, leading to proteolysis of the autoinhibitory domain of CnA. This causes an increase in CnA activity and results in nuclear translocation of CnA. Loss of the autoinhibitory domain renders CnA constitutively nuclear and active, even after removal of the hypertrophic stimulus. [less ▲]

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See detailCalcineurin in human heart hypertrophy.
Ritter, Oliver; Hack, Susanne; Schuh, Kai et al

in Circulation (2002), 105(19), 2265-9

BACKGROUND: In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be ... [more ▼]

BACKGROUND: In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. METHODS AND RESULTS: We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. CONCLUSIONS: Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy. [less ▲]

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See detailCommon genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease
Clee, S. M.; Zwinderman, A. H.; Engert, J. C. et al

in Circulation (2001), 103(9), 1198-1205

BACKGROUND: Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (ABCA1) as the major ... [more ▼]

BACKGROUND: Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (ABCA1) as the major gene underlying the HDL deficiency associated with reduced cholesterol efflux. Mutations within the ABCA1 gene are associated with decreased HDL-C, increased triglycerides, and an increased risk of CAD. However, the extent to which common variation within this gene influences plasma lipid levels and CAD in the general population is unknown. METHODS AND RESULTS: We examined the phenotypic effects of single nucleotide polymorphisms in the coding region of ABCA1. The R219K variant has a carrier frequency of 46% in Europeans. Carriers have a reduced severity of CAD, decreased focal (minimum obstruction diameter 1.81+/-0.35 versus 1.73+/-0.35 mm in noncarriers, P:=0.001) and diffuse atherosclerosis (mean segment diameter 2.77+/-0.37 versus 2.70+/-0.37 mm, P:=0.005), and fewer coronary events (50% versus 59%, P:=0.02). Atherosclerosis progresses more slowly in carriers of R219K than in noncarriers. Carriers have decreased triglyceride levels (1.42+/-0.49 versus 1.84+/-0.77 mmol/L, P:=0.001) and a trend toward increased HDL-C (0.91+/-0.22 versus 0.88+/-0.20 mmol/L, P:=0.12). Other single nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis. CONCLUSIONS: These data suggest that common variation in ABCA1 significantly influences plasma lipid levels and the severity of CAD. [less ▲]

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See detailThe methodology of mental stress testing in cardiovascular research.
Steptoe, Andrew; Vögele, Claus UL

in Circulation (1991), 83(Suppl II), 14-24

Many issues related to the selection, reliability, and validity of mental stress testing in cardiovascular research are discussed. Five categories of mental stress testing are distinguished: problem ... [more ▼]

Many issues related to the selection, reliability, and validity of mental stress testing in cardiovascular research are discussed. Five categories of mental stress testing are distinguished: problem-solving tasks, information-processing tasks, psychomotor tasks, affective conditions, and aversive or painful conditions. A series of practical and theoretical criteria are outlined for the selection of appropriate tests, and the measurement of a range of dependent variables is emphasized. The temporal stability of cardiovascular responses to mental stress tests is examined through an analysis of test-retest correlations (weighted for sample size) in 28 comparisons with intervals between sessions varying from 1 day to more than 1 year. Heart rate reactions to tasks show an average-weighted Z of 0.732 +/- 0.031 (r = 0.62), with Z = 0.575 +/- 0.034 (r = 0.52) for systolic blood pressure and Z = 0.313 +/- 0.035 (r = 0.30) for diastolic blood pressure. It is argued that the validity of mental stress tests can be judged in relation to several different aspects, specifically, methodological, ecological, diagnostic, prognostic, and therapeutic validities. The nature of these standards is described, and pertinent literature is presented. [less ▲]

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