Does arginase activity in vitro represent that in vivo?
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Animals↗
Biomedical subjects
David M Kaye
Publications and source records attributed to David M Kaye.
Antioxidant actions contribute to the antihypertrophic effects of atrial natriuretic peptide in neonatal rat cardiomyocytes.
OBJECTIVE: Reactive oxygen species (ROS) such as superoxide have been linked to the hypertrophic response of the heart to stimuli including angiotensin II (AngII), mechanical stretch, and pressure overload. We have previously demonstrated that cGMP and protein kinase G mediate the antihypertrophic actions of the natriuretic peptides in rat cardiomyocytes and isolated whole hearts. The impact of natriuretic peptides on cardiac ROS generation, however, has not been investigated. We tested the hypothesis that reduced superoxide accumulation contributes to the antihypertrophic action of atrial natriuretic peptide (ANP). METHODS: Neonatal rat cardiomyocytes were cultured in serum-free medium with and without AngII (1 micromol/L) or endothelin-1 (ET(1), 60 nmol/L) in the presence and absence of ANP (1 micromol/L) or tempol (100 micromol/L). Hypertrophic responses, cardiomyocyte superoxide generation, and cardiomyocyte expression of NADPH oxidase were determined. RESULTS: AngII induced increases in cardiomyocyte size (to 176 +/- 9% n = 8 p < 0.001, at 48 h), beta-myosin heavy chain expression (to 4.0 +/- 1.6-fold n = 6 p < 0.05, at 48 h), c-fos expression (to 1.9 +/- 0.5-fold n = 7 p < 0.01, at 6 h), superoxide generation (to 181+/-21% n = 8 p < 0.005, at 24 h), and expression of the gp91phox subunit of NADPH oxidase (to 2.4 +/- 0.5-fold n = 7 p < 0.05, at 48 h). These effects were all significantly inhibited by ANP: cardiomyocyte size, beta-myosin heavy chain expression, c-fos expression, superoxide generation and gp91phox expression were reduced to 107 +/- 5% (n = 5 p < 0.05), 1.2 +/- 0.2-fold (n = 6 p < 0.05), 0.9 +/- 0.2-fold (n = 7 p < 0.05), 141 +/- 21% (n = 8 p < 0.05), and to 1.0 +/- 0.5-fold (n = 7 p < 0.05), respectively. These effects were mimicked by tempol. ANP and tempol also significantly inhibited ET1-induced increases in cardiomyocyte size and superoxide generation, but had no effect on markers of hypertrophy when studied alone. CONCLUSION: This data indicates that the antihypertrophic actions of ANP are accompanied by reduced levels of superoxide, suggesting an antioxidant action contributes to the antihypertrophic actions of ANP.
Angiotensin II↗
Evaluation of sympathetic re-innervation in heterotopic cardiac transplants by iodine-123-metaiodobenzylguanidine (I-123-MIBG) imaging.
Scintigraphy using iodine-123-metaiodobenzylguanidine (I-123-MIBG) has been used to demonstrate that >50% of orthotopically transplanted hearts undergo partial cardiac sympathetic re-innervation and that this occurs no earlier than 1 year post-transplant. This study used planar and singe-photon emission computed tomography (SPECT) I-123 MIBG scintigraphy to show that cardiac re-innervation was not detectable in any of the 8 patients studied 1.1 to 6.3 years post-heterotopic transplantation. Thus, potential for cardiac re-innervation varies according to the type of procedure performed.
3-Iodobenzylguanidine↗
Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress.
Endothelial dysfunction is a hallmark of cardiovascular disease, and the l-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with l-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (P = 0.01) than nonsmokers, whereas citrulline (17%; P < 0.05) and N-hydroxy-l-arginine (34%; P < 0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-l-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial l-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease.
Adult↗
Feasibility and short-term efficacy of percutaneous mitral annular reduction for the therapy of functional mitral regurgitation in patients with heart failure.
BACKGROUND: While functional mitral regurgitation (MR) commonly accompanies heart failure and contributes to heart failure progression, mitral repair in the setting of HF is not routinely practiced because of the attendant significant morbidity and mortality. This limitation has fostered the development of percutaneous devices to reduce MR, and our group has recently reported the short- and long-term effectiveness of a percutaneous mitral annuloplasty device placed in the coronary sinus (Percutaneous Mitral Annuloplasty Device (PMAD), Cardiac Dimensions(R), Inc., Kirkland, WA) in reducing MR in experimental animal models of heart failure with associated MR. In this article, we report results of a "first-in-human" study of temporary placement of the PMAD device. The aim of this study was to demonstrate the feasibility and safety of temporary deployment of this device in patients with functional MR in association with heart failure. METHODS: Five patients undergoing scheduled coronary angiography with heart failure and functional MR (mean age 52 +/- 9 [SD] years) were recruited, and four had anatomy suitable for deployment of the device. Transthoracic echocardiography and coronary angiography were performed before and after temporary placement and tensioning of the PMAD via the right internal jugular vein. RESULTS: Temporary deployment of the device resulted in a significant reduction in the septal-lateral mitral annular dimension from 35.5 +/- 4.7 to 32.2 +/- 4.6 mm (P = 0.02), with evidence of a reduction in the MR color Doppler area from 98.3 +/- 43.6 to 83.3 +/- 35.1 mm(2) (P = 0.09). There were no complications. CONCLUSIONS: This first-in-human study of a novel device for percutaneous treatment of functional MR has shown that temporary placement of this device in the coronary sinus/great cardiac vein of patients with heart failure and MR is feasible and safe. Evidence of temporary reduction in MR and a reduction in mitral annular area indicate promise for device effectiveness in chronic implantation.
Feasibility Studies↗
Endothelial dysfunction and impaired L-arginine transport in hypertension and genetically predisposed normotensive subjects.
The term endothelial dysfunction (ED) generally refers to a pathological circumstance in which normal endothelial regulation of vasomotor tone is disturbed. ED has been described in a broad range of cardiovascular and related disease states. In association, deranged endothelial function also has the potential to result in abnormal platelet aggregation and monocyte adhesion. Over the past decade, it has become apparent that reduced availability of nitric oxide is a key mechanism for ED. A range of biochemical disturbances, including depressed L-arginine, have been shown to be associated with ED, and recent evidence indicates this may be genetically determined.
Arginine↗
Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation.
OBJECTIVE: In this study, we aimed to compare the level of atrial sympathetic innervation in human atrial fibrillation (AF) to that in sinus rhythm (SR). BACKGROUND: Histological studies of atrial tissue obtained from animals with experimentally induced AF indicate that sympathetic hyperinnervation could play a role in the pathogenesis of AF. METHODS: In 24 patients (12 in SR and 12 in AF) undergoing bypass surgery, we collected right atrial appendage tissue. In AF patients, left atrial appendage tissue was also acquired. The degree of sympathetic innervation was quantified by measuring the amount of staining for tyrosine hydroxylase (TH) and tissue norepinephrine (NE). In conjunction, nerve growth factor (NGF) mRNA expression was assessed by real-time polymerase chain reaction (PCR). Growth-associated protein 43 (GAP43) immunostaining was used to assess degree of new neural growth. RESULTS: When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort. The degree of atrial TH staining (P = 0.01) and NE content (P < 0.001) was also significantly greater in the right compared with left atrial samples in the AF cohort. There were no differences in NGF mRNA expression or GAP43 staining. CONCLUSION: This study provides evidence for the presence of heightened atrial sympathetic innervation in patients with persistent AF, suggesting autonomic remodeling may be part of atrial substrate for AF.
Adaptation, Physiological↗
Biventricular pacing in heart failure: a review.
Biventricular pacing has been an exciting recent advance in the management of drug-refractory heart failure. This new therapy has evolved as much from necessity as scientific observation, since benefits derived from pharmacotherapy currently appear to have reached their peak. Clinical trials of biventricular pacing are establishing morbidity and mortality benefits in heart failure. New challenges in the use of these pacemakers are now arising. These include the accurate diagnosis of ventricular dyssynchrony and, hence, potential responders to the refinement of implantation of the left ventricular lead to the appropriate dyssynchronous ventricular area and optimization of pacemaker programming. This review gives a general overview of the principles and the current evidence for the use of biventricular pacemakers in the treatment of heart failure. In addition, a discussion of current research and future projects is included.
Cardiac Pacing, Artificial↗
Development of a novel perfusion technique to allow targeted delivery of gene therapy--the V-Focus system.
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Adenoviridae↗
Subacute anthracycline cardiotoxicity.
We describe the case of 25-year-old man, with acute myeloid leukaemia, who presented with a myopericarditis syndrome 17 days post consolidation chemotherapy with high dose cytarabine and idarubicin. Transthoracic echocardiography showed marked transient increased left ventricular wall thickness associated with normal systolic contraction. In conjunction, pulsed tissue Doppler analysis revealed low early diastolic annular velocities, consistent with diastolic dysfunction. Endomyocardial biopsy showed severe interstitial myocardial oedema in the absence of a cellular infiltrate or myofibre damage. We believe this is the first case of subacute anthracycline toxicity described with the pathological findings of isolated myocardial oedema.
Adult↗
Atrial fibrillation impairs cardiac sympathetic response to baroreceptor unloading in congestive heart failure.
AIMS: In this study, we investigated for a potential mechanism by which atrial fibrillation (AF) might convey a worse prognosis in congestive heart failure (CHF). Specifically, we aimed to determine whether AF impaired cardiac sympathetic response to baroreceptor unloading in comparison to sinus rhythm (SR) in CHF. METHODS AND RESULTS: Eighteen CHF patients (ejection fraction 30+/-2%, age 59+/- 2 years), nine in SR and nine in AF, were enrolled. A right heart study and cardiac sympathetic tone assessment by coronary sinus catheter were performed at baseline and after 10 min of 20 degrees and 30 degrees of passive head up tilt (HUT). Filling pressures fell significantly during HUT in both SR and AF groups (AF, P=0.002; SR, P<0.001). The cardiac sympathetic response to HUT was significantly attenuated by AF compared with SR (P=0.014). In conjunction, right atrial appendages were collected from 23 cardiac surgery patients, 12 in SR and 11 in AF to investigate the presence of fibrosis. AF was associated with a significant increase in the collagen density (P=0.025). CONCLUSION: AF is associated with impaired cardiac sympathetic response to baroreceptor unloading compared with SR in CHF, possibly secondary to atrial fibrosis.
Atrial Fibrillation↗
Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation.
Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes. To test this, we examined 5- to 6-mo-old transgenic (TG) mice that overexpress NGF in heart and their wild-type (WT) littermates using echocardiography, invasive catheterization, histology, and catecholamine assays. In TG mice, hypertrophy of the right ventricle was evident (+67%), but the left ventricle was only mildly affected (+17%). Left ventricular (LV) fractional shortening and fractional area change values as indicated by echocardiography were similar between the two groups. Catheterization experiments revealed that LV +/-dP/dt values were comparable between TG and WT mice and responded similarly upon isoproterenol stimulation, which indicates lack of beta-adrenergic receptor dysfunction. Although norepinephrine levels in TG LV tissue were approximately twofold those of WT tissue, TG plasma levels of the neuronal norepinephrine metabolite dihydroxyphenylglycol were fivefold those of WT plasma. A greater neuronal uptake activity was also observed in TG LV tissue. In conclusion, overexpression of NGF in heart leads to sympathetic hyperinnervation that is not associated with detrimental effects on LV performance and is likely due to concomitantly enhanced norepinephrine neuronal uptake.
Adrenergic beta-Agonists↗
Augmentation of endothelial function following exercise training is associated with increased L-arginine transport in human heart failure.
We have reported previously a decrease in the clearance of the NO (nitric oxide) precursor L-arginine in the forearm circulation of CHF (congestive heart failure) patients, suggesting a potential rate-limiting mechanism contributing to the common finding of endothelial dysfunction in CHF. Given data that show exercise training augments endothelial function in CHF, the aim of the present study was to investigate whether these improvements were due to an increase in L-arginine transport. Measures of L-arginine transport, endothelial function and exercise capacity were repeated before and after 8 weeks of "usual living" or exercise training in 21 CHF patients [NYHA (New York Heart Association) class II/III]. Exercise capacity (6-min walk test) increased following exercise training (496+/-21 to 561+/-17 m; P=0.005), whereas the control group demonstrated no change [488+/-18 to 484+/-21 m; P=ns (not significant)]. Basal FBF (forearm blood flow) remained stable following exercise training (2.68+/-0.55 to 2.46+/-0.32 ml.min(-1).100 ml(-1) of tissue) and "usual living" (2.16+/-0.37 to 2.91+/-0.55 min(-1).100 ml(-1) of tissue). FBF responses to ACh (acetylcholine) increased following exercise by 49.6+/-17.7% (area under curve; P=0.01) demonstrating augmented endothelial function. FBF responses to SNP (sodium nitroprusside) were also improved following exercise training (30.8+/-8.2%; P=0.02). There was no change in vascular function in the "usual living" group. The clearance of L-arginine was significantly increased following involvement in the exercise programme (69.4+/-7.8 to 101.0+/-9.5 ml/min; P=0.04), whereas there was no change in the "usual living" group (78.4+/-17.5 to 81.0+/-14.9 ml/min; P=ns). In conclusion, the augmentation in endothelial function observed following exercise may be due, in part, to an increase in the transport of L-arginine in CHF patients.
Acetylcholine↗
Angiotensin II and norepinephrine release: interaction and effects on the heart.
BACKGROUND: Angiotensin (Ang) II may enhance the influence of the sympathetic nervous system at various levels by facilitating norepinephrine (NE) release. We investigated whether such an interaction is evident in the human heart and whether it has an impact on left ventricular (LV) structure. METHODS AND RESULTS: Ang I and Ang II concentrations were determined in arterial and coronary sinus (CS) plasma samples in a group of normotensive (n = 10) and hypertensive (n = 18) subjects. Total systemic and cardiac NE spillover was measured using isotope dilution methodology and LV structure by echocardiography. Arterial and CS concentrations of Ang I and Ang II were similar in both groups (Ang II CS, 5.8 +/- 4.0 versus 3.7 +/- 3.1 fmol/ml; P = not significant), as was the Ang II/Ang I ratio (CS, 0.56 +/- 0.17 versus 0.54 +/- 0.22 fmol/fmol; P = not significant). Total systemic (223 +/- 145 versus 374 +/- 149 ng/min; P < 0.05) and cardiac NE spillover (11.7 +/- 6.3 versus 19.4 +/- 10.5 ng/min; P < 0.05) were increased in hypertensive patients, as was LV mass index (LVMI) (86.7 +/- 14.7 versus 117.2 +/- 19.4 g/m; P < 0.001). LVMI correlated with cardiac NE spillover (r = 0.47; P < 0.02). No correlation was evident between CS Ang II and cardiac NE spillover (r = 0.001; P = not significant) or LVMI (r = -0.20; P = not significant). Arterial Ang II tended to correlate with total systemic NE spillover (r = 0.34; P = 0.081). When hypertensive subjects were divided into two groups with either high or low CS Ang II concentration, cardiac NE spillover and LVMI did not differ between the two groups. CONCLUSION: These findings suggest a growth-promoting effect of increased cardiac sympathetic tone on cardiomyocytes in hypertensive patients, but do not support the notion of a significant role of Ang II for norepinephrine release and LV hypertrophy in the hypertensive human heart.
Adult↗
Impaired L-arginine transport and endothelial function in hypertensive and genetically predisposed normotensive subjects.
BACKGROUND: Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor L-arginine is related to decreased endothelial function. METHODS AND RESULTS: Radiotracer kinetics ([3H]L-arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (n=12) and in 2 groups of healthy volunteers with (n=15) and without (n=15) a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of L-arginine. In vivo and in vitro measures of L-arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group; however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of L-arginine and N(G),N(G')-dimethylarginine (ADMA) did not differ between groups. L-arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. CONCLUSIONS: Similar to their hypertensive counterparts, normotensive individuals at high risk for the development of hypertension are characterized by impaired L-arginine transport, which may represent the link between a defective L-arginine/NO pathway and the onset of essential hypertension. The observed transport defect is not due to apparent alterations in CAT-1 expression or elevated endogenous ADMA.
Acetylcholine↗
Interaction between cardiac sympathetic drive and heart rate in heart failure: modulation by adrenergic receptor genotype.
OBJECTIVES: In the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine. BACKGROUND: Heightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the alpha(2)-, beta(1)-, and beta(2)-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (alpha(2) and beta(2)) and post-synaptically (beta(1) and beta(2)), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals. METHODS: We determined the beta(1)-, beta(2)-, and alpha(2C)-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method. RESULTS: We showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 beta(2)-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the beta(1)-adrenoceptor. The genotype of the alpha(2C)- and beta(2)-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves. CONCLUSIONS: For the first time, we show that beta(2)-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.
Adult↗
Percutaneous mitral annular reduction provides continued benefit in an ovine model of dilated cardiomyopathy.
BACKGROUND: Functional mitral valve regurgitation plays a key role in the symptomatic severity and progression of heart failure. In an ovine model of dilated cardiomyopathy, we examined the chronic functional consequences of mitral regurgitation reduction using a recently developed novel percutaneous mitral annular reduction (PMAR) device. METHODS AND RESULTS: Fourteen adult sheep were paced right ventricularly at 180 to 190 bpm for 5 weeks, leading to the development of moderate mitral valve regurgitation. After echocardiographic, hemodynamic, and neurohormonal analysis, 9 animals underwent PMAR. All animals were subsequently paced for another 28 days, and a final echocardiographic and hemodynamic study was conducted. Animals that had undergone PMAR showed significantly increased negative and positive dP/dt, whereas pulmonary capillary wedge pressure and mitral valve regurgitation were significantly reduced compared with those at device implant despite continued pacing. In conjunction, significant improvements in plasma norepinephrine and brain natriuretic peptide were apparent. CONCLUSIONS: The application of PMAR in animals with pacing-induced dilated cardiomyopathy and functional mitral valve regurgitation resulted in continued improvements in hemodynamic and neurohormonal parameters.
Animals↗
In vivo and in vitro evidence for ACh-stimulated L-arginine uptake.
Whereas L-arginine is clearly recognized as the precursor for nitric oxide synthesis, and its entry into endothelial cells via system y(+) transport is established, few data exist regarding the acute regulation of this transport process. We specifically investigated the effect of ACh and isoprenaline (Iso) on L-arginine uptake in the human forearm and in cultured bovine aortic endothelial cells (BAEC). Sixteen healthy males were studied. During a steady-state intra-arterial infusion of [(3)H]L-arginine (100 nCi/min), the effects of ACh (9.25 and 37 microg/min), Iso (25-50 and 200 microg/min), and sodium nitroprusside (SNP) (1-2 and 8 microg/min) on forearm plasma flow (FPF), L-[(3)H]arginine uptake, and L-[(3)H]citrulline release were determined. In parallel experiments, the effects of ACh, Iso, and SNP on L-[(3)H]arginine uptake were studied in BAEC. L-Arginine uptake was inversely related to FPF (r = -0.50; P < 0.005). At a similar FPF (ACh 56.82 +/- 9.25, Iso 58.49 +/- 5.56, SNP 57.92 +/- 4.96 ml/min; P = ns), intra-arterial ACh significantly increased forearm uptake of L-[(3)H]arginine (54,655 +/- 8,018 dpm/min), compared with that observed with either Iso (40,517.23 +/- 6,841 dpm/min; P = 0.01) or SNP (36,816 +/- 4,650 dpm/min; P = 0.011). This was associated with increased ACh-induced L-[(3)H]citrulline release compared with Iso and SNP (P = 0.046). Similarly, in BAEC, ACh significantly increased L-[(3)H]arginine uptake compared with control, Iso, or SNP (ACh 12.0 x 10(7) +/- 1.83 x 10(7) vs. control 6.67 x 10(7) +/- 1.16 x 10(7) vs. Iso 7.35 x 10(7) +/- 1.63 x 10(7) vs. SNP 6.01 x 10(7) +/- 1.11 x 10(7) fmol.min(-1).mg(-1) at 300 micromol/l L-arginine; P = 0.043). Taken together, these data indicate that ACh stimulates L-arginine uptake in cultured endothelial cells and in human forearm circulation, indicating the potential for acute modulation of endothelial L-arginine uptake.
Acetylcholine↗