Acute effects of angiotensin-converting enzyme inhibition versus angiotensin II receptor blockade on cardiac sympathetic activity in patients with heart failure.

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures (P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan (P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan (P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF.

ß-blockade restores muscle sympathetic rhythmicity in human heart failure.

BACKGROUND: Muscle sympathetic nerve firing rate increases as chronic heart failure (CHF) progresses, yet its oscillation, particularly within the frequency range encompassing 0.13 Hz, diminishes. The current study tested the hypothesis that chronic therapy with lipophilic ß-adrenoceptor antagonists augments the modulation of muscle sympathetic nerve activity variability (MSNAV) at this frequency range. METHODS AND RESULTS: In 21 CHF angiotensin converting enzyme (ACE) inhibitor-treated patients (age: 53 ± 2, ejection fraction: 20 ± 2%), MSNA was recorded before and after 4 months of ß-blockade with either metoprolol (up to 50mg b.i.d.) or carvedilol (up to 25mg b.i.d.). Harmonic MSNAV was assessed by coarse graining spectral analysis. Both drugs lowered heart rate similarly (-13 ± 2 beats/min; P < 0.001) but neither affected MSNA burst frequency (-7 ± 4 bursts/min, not significant). Before ß-blockade, harmonic MSNA power in the region encompassing 0.13 Hz was essentially absent. Beta-blockade increased the mean values for total power (from 0.00 to 0.50 Hz; 5.2 ± 0.8 to 6.8 ± 1.2U(2); P < 0.001) and for harmonic MSNA spectral power across the 0.1-0.22 Hz frequency range (from 0.48 ± 0.10 to 1.50 ± 0.32 U(2), F = 12.2; P < 0.001). Both carvedilol and metoprolol had a similar effect. CONCLUSIONS: In patients with CHF receiving ACE inhibitors, adding a ß-adrenoceptor antagonist restores low and high frequency harmonic oscillations in MSNA. Beta-1 antagonism is sufficient to achieve this response. Augmented modulation of sympathetic outflow could contribute to the beneficial effects of ß-blockade in CHF on sudden death and disease progression.

Sudden cardiac death in dilated cardiomyopathies.

Dilated cardiomyopathy (DCM) is the most prevalent form of cardiomyopathy, and sudden cardiac death (SCD) remains a common event in young patients. The disorder is highly heterogeneous and pediatric DCM often differs from adult DCM in etiologies, risk factors, and prognosis. Prognosis may be improving, likely secondary to specialized management. Both traditional and novel markers of risk have been studied in adults and are beginning to be applied to children with DCM. The major therapy for patients considered at risk remains implantable cardioverter-defibrillator (ICD) placement, although frequently this functions as a bridge to eventual transplantation.

GH43 endo-arabinanase from Bacillus licheniformis: Structure, activity and unexpected synergistic effect on cellulose enzymatic hydrolysis.

The hydrolysis of the plant biomass provides many interesting opportunities for the generation of building blocks for the green chemistry industrial applications. An important progress has been made for the hydrolysis of the cellulosic component of the biomass while, for the hemicellulosic components, the advances are less straightforward. Here, we describe the cloning, expression and biochemical and structural characterization of BlAbn1, a GH43 arabinanase from Bacillus licheniformis. This enzyme is selective for linear arabinan and efficiently hydrolyzes this substrate, with a specific activity of 127 U/mg. The enzyme has optimal conditions for activity at pH 8.0 and 45 °C and its activity is only partially dependent of a bound calcium ion since 70% of the maximal activity is preserved even when 1 mM EDTA is added to the reaction medium. BlAbn1 crystal structure revealed a typical GH43 fold and narrow active site, which explains the selectivity for linear substrates. Unexpectedly, the enzyme showed a synergic effect with the commercial cocktail Accellerase 1500 on cellulose hydrolysis. Scanning Electron Microscopy, Solid-State NMR and relaxometry data indicate that the enzyme weakens the interaction between cellulose fibers in filter paper, thus providing an increased access to the cellulases of the cocktail.

The effects of dobutamine on cardiac sympathetic activity in patients with congestive heart failure.

OBJECTIVES: The goal of this work was to study the effects of short-term infusion of dobutamine on efferent cardiac sympathetic activity. BACKGROUND: Increased efferent cardiac sympathetic activity is associated with poor outcomes in the setting of congestive heart failure (CHF). Dobutamine is commonly used in the therapy of decompensated CHF. Dobutamine, through its effects on excitatory beta-receptors, may increase cardiac sympathetic activity. METHODS: Seven patients with normal left ventricular (LV) function and 13 patients with CHF were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) before and during an intravenous infusion of dobutamine titrated to increase the rate of rise in LV peak positive pressure (+dP/dt) by 40%. RESULTS: Systemic arterial pulse pressure increased significantly in response to dobutamine in the normal LV function group (74 +/- 3 mm Hg to 85 +/- 3 mm Hg, p = 0.005) but remained unchanged in the CHF group. Dobutamine caused a significant decrease in LV end-diastolic pressure in the CHF group (14 +/- 2 mm Hg to 11 +/- 2 mm Hg, p = 0.02), an effect not observed in the normal LV group. In the normal LV function group, CANESP did not change in response to dobutamine (75 +/- 22 pmol/min vs. 72 +/- 22 pmol/min, p = NS). In contrast, dobutamine infusion was associated with a significant reduction in CANESP in patients with CHF (199 +/- 43 pmol/min to 128 +/- 30 pmol/min, p < 0.0009). CONCLUSIONS: Dobutamine infusion caused a significant sympatholytic response in patients with CHF. This sympathetic withdrawal response is probably related to reduction of LV filling pressures and/or activation of ventricular mechanoreceptors with dobutamine infusion.

Selective versus nonselective beta-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization.

BACKGROUND: Non-selective and selective beta-blockers have been shown to improve outcomes in chronic heart failure (CHF). Recent data suggests the non-selective beta-blockers have a more favourable effect on outcomes than beta(1)-selective agents. We sought to examine the differential effects of non-selective versus selective beta-blockade on myocardial substrate utilization in patients with CHF. METHODS AND RESULTS: Twenty-two patients with CHF were randomised to the non-selective beta-blocker carvedilol or the selective beta-blocker metoprolol (double-blind). Measurement of hemodynamics, arterial and coronary sinus free fatty acid (FFA) and lactate levels, and cardiac norepinephrine spillover (CANESP) were made before and after 4 months of therapy. In the carvedilol group (n=11), there was a significant reduction in myocardial FFA uptake (0.12+/-0.02 to 0.1+/-0.02 mmol/l, P<0.03). By contrast, in the metoprolol group (n=11) there was no change in myocardial FFA extraction. Carvedilol therapy tended to increase myocardial lactate extraction (0.24+/-0.05 to 0.35+/-0.08 mmol/l, P=0.08) while metoprolol therapy resulted in a trend in the opposite direction (0.18+/-0.03 to 0.11+/-0.04 mmol/l, P=0.09). The change in lactate extraction in the carvedilol group was significantly different from that in the metoprolol group (+0.11+/-0.06 vs. -0.09+/-0.04 mmol/l, P<0.01). Carvedilol treatment caused a significant reduction in CANESP while metoprolol had a neutral effect (-95+/-27 vs. 25+/-42 pmol/min, carvedilol vs. metoprolol P<0.03). CONCLUSION: Carvedilol treatment caused a 20% reduction in myocardial free fatty acid extraction while metoprolol had a neutral effect. These differences are most probably related to the differential effects of these two agents on efferent cardiac sympathetic activity and may be relevant to the reported differential effects of these drugs on clinical outcomes.

Vagal heart rate responses to chronic beta-blockade in human heart failure relate to cardiac norepinephrine spillover.

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P<0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.

Difference-NMR techniques for selection of components on the basis of relaxation times.

This work describes a numerical methodology to obtain more efficient relaxation filters to selectively retain or remove components based on relaxation times. The procedure uses linear combinations of spectra with various recycle or filter delays to obtain components that are both quantitative and pure. Modulation profiles are calculated assuming exponential relaxation behavior. The method is general and can be applied to a wide range of solution or solid-state NMR experiments including direct-polarization (DP), or filtered cross-polarization (CP) spectra. 13C NMR experiments on isotactic poly(1-butene) and dimethyl sulfone showed the utility of the technique for selectively suppressing peaks.

Left ventricular isovolumic relaxation is a predictor of left ventricular end-diastolic pressure.

BACKGROUND: The relationship between isovolumic left ventricular (LV) relaxation and LV filling pressures remains incompletely explored. If there is a relationship between the rate of early diastolic LV relaxation and LV end-diastolic pressure, this would have important implications concerning both our understanding and, potentially, our treatment of LV diastolic dysfunction. OBJECTIVE: To examine the baseline hemodynamic correlates of LV end-diastolic pressure in patients with both normal and abnormal LV function. METHODS: The relationships between LV end-diastolic pressure, a variety of hemodynamic parameters (tau, the rate of LV isovolumic relaxation, LV peak positive+dP/dt, LV peak systolic pressure and heart rate), measures of LV end-systolic and end-diastolic volume, and age were determined using regression analysis techniques in 104 patients with normal LV systolic function and 90 patients with an LV ejection fraction of less than 40%. RESULTS: Univariate analysis demonstrated a correlation between tau and LV end-diastolic pressure (r=0.743, P<0.001). There were significant univariate relationships between a number of other hemodynamic variables and LV end-diastolic pressure. A multiple regression model demonstrated that tau made the most important contribution to a model where LV end-diastolic pressure is the dependent variable. LV peak systolic pressure and heart rate also made significant contributions to the model. In 33 of these patients, when LV end-diastolic pressure was reduced using an inferior vena cava occlusion balloon, tau did not change. The acute administration of clonidine (n=11) caused an increase in LV end-diastolic pressure that was closely correlated with an observed increase in tau (r=0.843, P<0.001). CONCLUSIONS: These observations suggest that the rate of LV isovolumic relaxation is a predictor of LV end-diastolic pressure.

Effects of nitroprusside on cardiac norepinephrine spillover and isovolumic left ventricular relaxation in the normal and failing human left ventricle.

BACKGROUND: Left ventricular isovolumic relaxation responses to changes in afterload or preload may be mediated, in part, by reflex changes in sympathetic nervous system activity. PATIENTS AND METHODS: The authors examined whether changes in left ventricular isovolumic relaxation during changes in load were associated with changes in cardiac norepinephrine spillover. Six patients with normal left ventricular function and 12 patients with congestive heart failure secondary to left ventricular systolic dysfunction were studied. Measurements of left ventricular isovolumic relaxation (Tau) were obtained using a high fidelity left ventricular pressure manometer, before, during and after infusion of nitroprusside. Total body and cardiac norepinephrine spillover were measured using a radiotracer infusion. RESULTS: Nitroprusside caused significant reductions in systemic arterial and left ventricular end-diastolic pressures, changes that were similar in the two groups. In people with normal left ventricular systolic function, these changes were associated with significant increases in both systemic and cardiac sympathetic activity, but no change in Tau. In the group with congestive heart failure, cardiac norepinephrine spillover did not change; however, there was a significant increase in the rate of left ventricular isovolumic relaxation. CONCLUSION: This study confirms that in the failing human left ventricular, isovolumetric relaxation is sensitive to changes in loading conditions induced by the nitrosovasodilator nitroprusside. Importantly, this load sensitivity is not associated with reflex increases in cardiac sympathetic activity.

Multi-scale structural and chemical analysis of sugarcane bagasse in the process of sequential acid-base pretreatment and ethanol production by Scheffersomyces shehatae and Saccharomyces cerevisiae.

BACKGROUND: Heavy usage of gasoline, burgeoning fuel prices, and environmental issues have paved the way for the exploration of cellulosic ethanol. Cellulosic ethanol production technologies are emerging and require continued technological advancements. One of the most challenging issues is the pretreatment of lignocellulosic biomass for the desired sugars yields after enzymatic hydrolysis. We hypothesized that consecutive dilute sulfuric acid-dilute sodium hydroxide pretreatment would overcome the native recalcitrance of sugarcane bagasse (SB) by enhancing cellulase accessibility of the embedded cellulosic microfibrils. RESULTS: SB hemicellulosic hydrolysate after concentration by vacuum evaporation and detoxification showed 30.89 g/l xylose along with other products (0.32 g/l glucose, 2.31 g/l arabinose, and 1.26 g/l acetic acid). The recovered cellulignin was subsequently delignified by sodium hydroxide mediated pretreatment. The acid-base pretreated material released 48.50 g/l total reducing sugars (0.91 g sugars/g cellulose amount in SB) after enzymatic hydrolysis. Ultra-structural mapping of acid-base pretreated and enzyme hydrolyzed SB by microscopic analysis (scanning electron microcopy (SEM), transmitted light microscopy (TLM), and spectroscopic analysis (X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Fourier transform near-infrared (FT-NIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy) elucidated the molecular changes in hemicellulose, cellulose, and lignin components of bagasse. The detoxified hemicellulosic hydrolysate was fermented by Scheffersomyces shehatae (syn. Candida shehatae UFMG HM 52.2) and resulted in 9.11 g/l ethanol production (yield 0.38 g/g) after 48 hours of fermentation. Enzymatic hydrolysate when fermented by Saccharomyces cerevisiae 174 revealed 8.13 g/l ethanol (yield 0.22 g/g) after 72 hours of fermentation. CONCLUSIONS: Multi-scale structural studies of SB after sequential acid-base pretreatment and enzymatic hydrolysis showed marked changes in hemicellulose and lignin removal at molecular level. The cellulosic material showed high saccharification efficiency after enzymatic hydrolysis. Hemicellulosic and cellulosic hydrolysates revealed moderate ethanol production by S. shehatae and S. cerevisiae under batch fermentation conditions.

Molecular Dynamics of Poly(Ethylene Glycol) Intercalated in Clay, Studied Using 13C Solid-State NMR.

In this study, Cross-Polarization Magic-angle Spinning CP/MAS, 2D Exchange, Centerband-Only Detection of Exchange (CODEX), and Separated-Local-Field (SLF) NMR experiments were used to study the molecular dynamics of poly(ethylene glycol) (PEG) inside Hectorite/PEG intercalation compounds in both single- and double-layer configurations. The results revealed that the overall amplitude of the motions of the PEG chain in the single-layer configuration is considerably smaller than that observed for the double-layer intercalation compound. This result indicates that the effect of having the polymer chain interacting with both clay platelets is to produce a substantial decrease in the motional amplitudes of those chains. The presence of these dynamically restricted segments might be explained by the presence of anchoring points between the clay platelets and the PEG oxygen atoms, which was induced by the Na⁺ cations. By comparing the PEG motional amplitudes of the double-layered nanocomposites composed of polymers with different molecular weights, a decrease in the motional amplitude for the smaller PEG chain was observed, which might also be understood using the presence of anchoring points.

Cardiac-specific sympathetic activation in men and women with and without heart failure.

BACKGROUND: Clinical outcomes for cardiovascular syndromes such as heart failure differ between men and women. OBJECTIVE: To seek phenotypic evidence for sex-differences in cardiac-specific sympathetic nervous system activation, as abnormal sympathetic nervous system activation is a key pathophysiological mechanism in heart failure (HF). METHODS: Patients who underwent evaluation of cardiac norepinephrine spillover (CNESP) using radiotracer methodology were identified retrospectively, and included in the analysis if they met criteria for either a normal left ventricular (NLV) function group, or systolic HF group, defined as an LV ejection fraction <40% and NYHA class II-III symptoms. Within each group a matched cohort analysis, identifying two control men for each woman, was performed. RESULTS: 166 subjects were identified, 48 within the NLV function group and 118 within the HF group. In the NLV function group, 12 women were matched for age to 24 men. Women had significantly higher NE concentrations in coronary sinus plasma. When normalised to total body NE spillover (CNESP:TBNESP), women had significantly higher values than men (CNESP:TBNESP, 6±3% in women vs 3±3% in men, p<0.05). In the HF group, 20 women were matched for age, date of study and presence of coronary disease to 39 men. There were no differences in comorbidities, drugs or haemodynamic measurements. Both CNESP and CNESP:TBNESP were significantly higher in women with HF than in men (CNESP 264±191 in women vs 182±110 in men, CNESP:TBNESP 9±6% in women vs 4±2% in men, p<0.05 for both). CONCLUSION: In patients with and without HF, women exhibit increased cardiac-specific sympathetic activation. Sexual dimorphism in cardiac autonomic physiology and its relationship to disease merits further investigation.

Relationship between sodium intake and sleep apnea in patients with heart failure.

OBJECTIVES: The purpose of this study was to test the hypothesis that severity of sleep apnea (SA), assessed by frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]), is related to sodium intake in patients with heart failure (HF). BACKGROUND: Dependent edema and overnight rostral fluid shift from the legs correlate with the AHI in patients with HF in whom excessive sodium intake can cause fluid retention. METHODS: Sodium intake was estimated by food recordings in 54 HF patients who underwent overnight polysomnography. RESULTS: Thirty-one of the 54 patients had SA, and their mean sodium intake was higher than that in those without SA (3.0 ± 1.2 g vs. 1.9 ± 0.8 g, p < 0.001). There was a significant correlation between the AHI and sodium intake (r = 0.522, p < 0.001). Multivariate analysis showed that the significant independent correlates of the AHI were sodium intake, male sex, and serum creatinine level. CONCLUSIONS: These findings suggest that in patients with HF, sodium intake plays a role in the pathogenesis of SA.

A high-sodium diet is associated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study.

BACKGROUND: A low-sodium diet is an accepted treatment of patients with heart failure (HF), although minimal evidence exists on the appropriate amount of sodium intake for this population. Certain HF guidelines have liberalized dietary sodium recommendations, which actually exceed guidelines for healthy adults. OBJECTIVES: We tested the hypothesis that high sodium intake is related to acute decompensated HF (ADHF) in ambulatory HF patients. Secondary outcomes included all-cause hospitalization and mortality. DESIGN: We prospectively enrolled medically stable, ambulatory patients with systolic HF (n = 123; mean ± SD age: 60 ± 13 y) from 2 outpatient HF clinics from 2003 to 2007. Baseline estimates of dietary sodium and other nutrient intakes were obtained from two 3-d food records. RESULTS: The median follow-up time was 3.0 y. Mean (±SD) sodium intakes were 1.4 ± 0.3, 2.4 ± 0.3, and 3.8 ± 0.8 g Na/d in the lower, middle, and upper tertiles, respectively. Cumulative ADHF event rates at 3 y were 12 ± 6%, 15 ± 7%, and 46 ± 11% in the low, middle, and upper tertiles, respectively (log-rank P = 0.001). For ADHF, the upper tertile was associated with an adjusted hazard ratio of 2.55 (95% CI: 1.61, 4.04; P < 0.001). Time-to-event probabilities were significant for mortality (log-rank P = 0.022) but not for all-cause hospitalization (log-rank P = 0.224). The high-sodium tertile was associated with an adjusted hazard ratio of 1.39 (95% CI: 1.06, 1.83; P = 0.018) for all-cause hospitalization and 3.54 (95% CI: 1.46, 8.62; P = 0.005) for mortality. CONCLUSIONS: To our knowledge, this study provides the first prospective evidence that ambulatory HF patients who consume higher amounts of sodium are at greater risk of an ADHF event. These data provide support for more stringent sodium intake guidelines than those currently recommended for HF patients.

The mobility of chondroitin sulfate in articular and artificial cartilage characterized by 13C magic-angle spinning NMR spectroscopy.

We have studied the molecular dynamics of one of the major macromolecules in articular cartilage, chondroitin sulfate. Applying (13)C high-resolution magic-angle spinning NMR techniques, the NMR signals of all rigid macromolecules in cartilage can be suppressed, allowing the exclusive detection of the highly mobile chondroitin sulfate. The technique is also used to detect the chondroitin sulfate in artificial tissue-engineered cartilage. The tissue-engineered material that is based on matrix producing chondrocytes cultured in a collagen gel should provide properties as close as possible to those of the natural cartilage. Nuclear relaxation times of the chondroitin sulfate were determined for both tissues. Although T(1) relaxation times are rather similar, the T(2) relaxation in tissue-engineered cartilage is significantly shorter. This suggests that the motions of chondroitin sulfate in natural and artificial cartilage are different. The nuclear relaxation times of chondroitin sulfate in natural and tissue-engineered cartilage were modeled using a broad distribution function for the motional correlation times. Although the description of the microscopic molecular dynamics of the chondroitin sulfate in natural and artificial cartilage required the identical broad distribution functions for the correlation times of motion, significant differences in the correlation times of motion that are extracted from the model indicate that the artificial tissue does not fully meet the standards of the natural ideal. This could also be confirmed by macroscopic biomechanical elasticity measurements. Nevertheless, these results suggest that NMR is a useful tool for the investigation of the quality of artificially engineered tissue.