Exercise Rehabilitation Improves Cardiac Volumes and Functional Capacity in Patients With Endomyocardial Fibrosis: A RANDOMIZED CONTROLLED TRIAL.

PURPOSE: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy associated with low functional capacity and high mortality rates. Exercise training has been proved to be a nonpharmacological treatment of cardiovascular diseases. Therefore, the purpose of this study was to determine the effects of exercise rehabilitation in EMF patients. METHODS: Twenty-two EMF patients, functional classes II and III (New York Heart Association [NYHA]), were randomized to the control (C-EMF) or exercise rehabilitation (Rehab-EMF) group. Patients in the Rehab-EMF group underwent 4 mo of exercise rehabilitation, whereas patients in the C-EMF group were instructed to maintain their usual daily routine. Peak oxygen uptake ((Equation is included in full-text article.)O2), cardiac function, and quality of life were evaluated. All assessments were performed at baseline and after 4 mo. RESULTS: After 4 mo of rehabilitation, peak (Equation is included in full-text article.)O2 increased in the Rehab-EMF group (17.4 ± 3.0 to 19.7 ± 4.4 mL/kg/min, P < .001), whereas the C-EMF group showed no difference (15.3 ± 3.0 to 15.0 ± 2.0 mL/kg/min, P = .87). Also, post-intervention, peak (Equation is included in full-text article.)O2 in the Rehab-EMF group was greater than that in the C-EMF group (P < .001). Furthermore, the Rehab-EMF group, when compared to the C-EMF group, showed an increase in left ventricular end-diastolic volume (102.1 ± 64.6 to 136.2 ± 75.8 mL vs 114.4 ± 55.0 to 100.4 ± 49.9 mL, P < .001, respectively) and decrease in left atrial diastolic volume (69.0 ± 33.0 to 34.9 ± 15.0 mL vs 44.6 ± 21.0 to 45.6 ± 23.0 mL, P < .001, respectively). Quality-of-life scores also improved in the Rehab-EMF group, whereas the C-EMF group showed no change (45 ± 23 to 27 ± 15 vs 47 ± 15 to 45 ± 17, P < .001, respectively). CONCLUSION: Exercise rehabilitation is a nonpharmacological intervention that improves functional capacity, cardiac volumes, and quality of life in EMF patients after endocardial resection surgery. In addition, exercise rehabilitation should be prescribed to EMF patients to improve their clinical condition.

Usnic acid-loaded polyaniline/polyurethane foam wound dressing: preparation and bactericidal activity.

The improved bactericidal activity of new composites for wound dressing prototypes represents an important strategy for development of more efficient devices that make use of synergistic interaction between components. The doping level of polyaniline represents a critical parameter for its corresponding biologic activity. In this work, it is explored the doping effect of usnic acid on undoped polyaniline, that introduces important advantages namely, improved bactericidal activity of polyaniline and the anti-biofilm properties of lichen derivative. The deposition of the resulting material on polyurethane foam potentializes its applicability as wound dressing, characterizing a new platform for application against Escherichia coli and Staphylococcus aureus.

Anorexia, functional capacity, and clinical outcome in patients with chronic heart failure: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF).

AIMS: We aimed to assess determinants of anorexia, that is loss of appetite in patients with heart failure (HF) and aimed to further elucidate the association between anorexia, functional capacity, and outcomes in affected patients. METHODS AND RESULTS: We assessed anorexia status among 166 patients with HF (25 female, 66 ± 12 years) who participated in the Studies Investigating Co-morbidities Aggravating HF. Anorexia was assessed by a 6-point Likert scale (ranging from 0 to 5), wherein values ≥1 indicate anorexia. Functional capacity was assessed as peak oxygen uptake (peak VO2 ), 6 min walk test, and short physical performance battery test. A total of 57 patients (34%) reported any anorexia, and these patients showed lower values of peak VO2 , 6 min walk distance, and short physical performance battery score (all P < 0.05). Using multivariate analysis adjusting for clinically important factors, only high-sensitivity C-reactive protein [odds ratio (OR) 1.24, P = 0.04], use of loop diuretics (OR 5.76, P = 0.03), and the presence of cachexia (OR 2.53, P = 0.04) remained independent predictors of anorexia. A total of 22 patients (13%) died during a mean follow-up of 22.5 ± 5.1 months. Kaplan-Meier curves for cumulative survival showed that those patients with anorexia presented higher mortality (Log-rank test P = 0.03). CONCLUSIONS: Inflammation, use of loop diuretics, and cachexia are associated with an increased likelihood of anorexia in patients with HF, and patients with anorexia showed impaired functional capacity and poor outcomes.

Cardiac and peripheral autonomic control in restrictive cardiomyopathy.

AIMS: Autonomic dysfunction determines the advance of dilated cardiomyopathy (DCM) and is related to poor outcomes. However, this autonomic imbalance is unknown in patients with restrictive cardiomyopathy (RCM) even though they have similar symptoms and poor quality of life as DCM patients have. The aim of this study was to evaluate if autonomic and neurovascular controls were altered in RCM patients. METHODS AND RESULTS: Fifteen RCM patients, 10 DCM patients, and 10 healthy subjects were evaluated. Heart rate and blood pressure (BP) were recorded. Peripheral sympathetic activity [muscle sympathetic nerve activity (MSNA)] by microneurography and cardiac sympathetic activity by power spectrum analysis of heart rate variability. Spontaneous baroreflex sensitivity (BRS) was evaluated by the sequence method and forearm blood flow by venous occlusion plethysmography. Both cardiomyopathy groups had higher MSNA frequency (P < 0.001) and MSNA incidence (P < 0.001), higher cardiac sympathovagal balance (P < 0.02), reduced BRS for increase (P = 0.002) and for decrease in BP (P = 0.002), and lower forearm blood flow (P < 0.001) compared with healthy subjects. We found an inverse correlation between BRS for increase and decrease in BP and peripheral sympathetic activity (r = -0.609, P = 0.001 and r = -0.648, P < 0.001, respectively) and between BRS for increase and decrease in BP and cardiac sympathetic activity (r = -0.503, P = 0.03 and r = -0.487, P = 0.04, respectively). CONCLUSIONS: The RCM patients had cardiac and peripheral autonomic dysfunctions associated with peripheral vasoconstriction. Nonetheless, the presence of normal ejection fraction underestimates the evolution of the disease and makes clinical treatment difficult. These alterations could lead to a similar cardiovascular risk as that observed in DCM patients.

3-Hy-droxy-2-phenyl-2,3,3a,7a-tetra-hydro-1H,5H-pyrano[3,2-b]pyrrol-5-one: crystal structure and Hirshfeld surface analysis.

The title isoaltholactone derivative, C13H13NO3, has an NH group in place of the ether-O atom in the five-membered ring of the natural product. The five-membered ring is twisted about the N-C bond linking it to the six-membered ring, which has a half-chair conformation with the O atom connected to the ether-O atom lying above the plane defined by the remaining atoms. The dihedral angle between the mean planes of the rings comprising the fused-ring system is 75.10 (8)°. In the crystal, hy-droxy-O-H⋯N(amine) hydrogen bonding sustains linear supra-molecular chains along the a axis. Chains are linked into a three-dimensional architecture via amine-N-H⋯π(phen-yl) and phenyl-C-H⋯O(hy-droxy) inter-actions. The influence of the amine-N-H⋯π(phen-yl) contact on the mol-ecular packing is revealed by an analysis of the Hirshfeld surface.

Muscle wasting and cachexia in heart failure: mechanisms and therapies.

Body wasting is a serious complication that affects a large proportion of patients with heart failure. Muscle wasting, also known as sarcopenia, is the loss of muscle mass and strength, whereas cachexia describes loss of weight. After reaching guideline-recommended doses of heart failure therapies, the most promising approach to treating body wasting seems to be combined therapy that includes exercise, nutritional counselling, and drug treatment. Nutritional considerations include avoiding excessive salt and fluid intake, and replenishment of deficiencies in trace elements. Administration of omega-3 polyunsaturated fatty acids is beneficial in selected patients. High-calorific nutritional supplements can also be useful. The prescription of aerobic exercise training that provokes mild or moderate breathlessness has good scientific support. Drugs with potential benefit in the treatment of body wasting that have been tested in clinical studies in patients with heart failure include testosterone, ghrelin, recombinant human growth hormone, essential amino acids, and ß2-adrenergic receptor agonists. In this Review, we summarize the pathophysiological mechanisms of muscle wasting and cachexia in heart failure, and highlight the potential treatment strategies. We aim to provide clinicians with the relevant information on body wasting to understand and treat these conditions in patients with heart failure.

Sarcopenia and Endothelial Function in Patients With Chronic Heart Failure: Results From the Studies Investigating Comorbidities Aggravating Heart Failure (SICA-HF).

OBJECTIVES: Skeletal muscle wasting, also known as sarcopenia, has recently been identified as a serious comorbidity in patients with heart failure (HF). We aimed to assess the impact of sarcopenia on endothelial dysfunction in patients with HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). DESIGN: Cross-sectional study. SETTING: Ambulatory patients with HF were recruited at Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany. PARTICIPANTS: We assessed peripheral blood flow (arm and leg) in 228 patients with HF and 32 controls who participated in the Studies Investigating Comorbidities Aggravating HF (SICA-HF). MEASUREMENTS: The appendicular skeletal muscle mass of the arms and the legs combined was assessed by dual energy x-ray absorptiometry (DEXA). Sarcopenia was defined as the appendicular muscle mass two standard deviations below the mean of a healthy reference group of adults aged 18 to 40 years, as suggested for the diagnosis of muscle wasting in healthy aging. All patients underwent a 6-minute walk test and spiroergometry testing. Forearm and leg blood flow were measured by venous occlusion plethysmography. Peak blood flow was assessed after a period of ischemia in the limbs to test endothelial function. RESULTS: Sarcopenia was identified in 37 patients (19.5%). Patients with sarcopenia presented with lower baseline forearm blood flow (2.30 ± 1.21 vs. 3.06 ± 1.49 vs. 4.00 ± 1.66 mL min-1 100 mL-1; P = .02) than those without sarcopenia or controls. The group of patients with sarcopenia showed similar baseline leg blood flow (2.06 ± 1.62 vs. 2.39 ± 1.39 mL min-1 100 mL-1; P = .11) to those without but lower values when compared to controls (2.06 ± 1.62 vs. 2.99 ± 1.28 mL min-1 100 mL-1; P = .03). In addition, patients with and without sarcopenia presented with lower peak flow in the forearm when compared to controls (18.37 ± 7.07 vs. 22.19 ± 8.64 vs. 33.63 ± 8.57 mL min-1 100 mL-1; P < .001). A similar result was observed in the leg (10.89 ± 5.61 vs. 14.66 ± 7.19 vs. 21.37 ± 13.16 mL min-1 100 mL-1; P < .001). Peak flow in the forearm showed a significant correlation with exercise capacity (relative peak VO2: R = 0.47; P < .001; absolute peak VO2: R = 0.35; P < .001; and 6-min walk distance: R = 0.20; P < .01). Similar correlations were observed between peak flow in the leg and exercise capacity (absolute peak VO2: R = 0.42, P < .001; relative peak VO2: R = 0.41, P < .001; and 6-min walk test: R = 0.33; P < .001). Logistic regression showed peak flow in the leg to be independently associated with the 6-min walk distance adjusted for age, hemoglobin level, albumin, creatinine, presence of sarcopenia, and coronary artery disease (hazard ratio, 0.903; 95% confidence interval, 0.835-0.976; P = .01). CONCLUSION: Patients with HF associated with sarcopenia have impaired endothelial function. Lower vasodilatation had a negative impact on exercise capacity, particularly prevalent in patients with sarcopenia.

Prolonged Practice of Swimming Is Negatively Related to Bone Mineral Density Gains in Adolescents.

BACKGROUND: The practice of swimming in "hypogravity" conditions has potential to decrease bone formation because it decreases the time engaged in weight-bearing activities usually observed in the daily activities of adolescents. Therefore, adolescents competing in national levels would be more exposed to these deleterious effects, because they are engaged in long routines of training during most part of the year. To analyze the effect of swimming on bone mineral density (BMD) gain among adolescents engaged in national level competitions during a 9-month period. METHODS: Fifty-five adolescents; the control group contained 29 adolescents and the swimming group was composed of 26 athletes. During the cohort study, BMD, body fat (BF) and fat free mass (FFM) were assessed using a dual-energy x-ray absorptiometry scanner. Body weight was measured with an electronic scale, and height was assessed using a stadiometer. RESULTS: During the follow-up, swimmers presented higher gains in FFM (Control 2.35 kg vs. Swimming 5.14 kg; large effect size [eta-squared (ES-r)=0.168]) and BMD-Spine (Swimming 0.087 g/cm(2) vs. Control 0.049 g/cm(2); large effect size [ES-r=0.167]) compared to control group. Male swimmers gained more FFM (Male 10.63% vs. Female 3.39%) and BMD-Spine (Male 8.47% vs. Female 4.32%) than females. Longer participation in swimming negatively affected gains in upper limbs among males (r=-0.438 [-0.693 to -0.085]), and in spine among females (r=-0.651 [-0.908 to -0.036]). CONCLUSIONS: Over a 9-month follow-up, BMD and FFM gains were more evident in male swimmers, while longer engagement in swimming negatively affected BMD gains, independently of sex.

Effect of Exercise Training and Testosterone Replacement on Skeletal Muscle Wasting in Patients With Heart Failure With Testosterone Deficiency.

OBJECTIVE: To examine whether combined testosterone replacement and exercise training (ET) therapies would potentiate the beneficial effects of isolated therapies on neurovascular control and muscle wasting in patients with heart failure (HF) with testosterone deficiency. PATIENTS AND METHODS: From January 10, 2010, through July 25, 2013, 39 male patients with HF, New York Heart Association functional class III, total testosterone level less than 249 ng/dL (to convert to nmol/L, multiply by .03467), and free testosterone level less than 131 pmol/L were randomized to training (4-month cycloergometer training), testosterone (intramuscular injection of testosterone undecylate for 4 months), and training + testosterone groups. Muscle sympathetic nerve activity was measured using microneurography, forearm blood flow using plethysmography, body composition using dual X-ray absorptiometry, and functional capacity using cardiopulmonary test. Skeletal muscle biopsy was performed in the vastus lateralis. RESULTS: Muscle sympathetic nerve activity decreased in ET groups (training, P<.01; training + testosterone, P<.01), whereas no changes were observed in the testosterone group (P=.89). Forearm blood flow was similar in all groups. Lean mass increased in ET groups (training, P<.01; training + testosterone, P<.01), whereas lean mass decreased in the testosterone group (P<.01). The response of cross-sectional area of type I (P<.01) and type II (P<.05) fibers increased in the training + testosterone group as compared with the isolated testosterone group. CONCLUSION: Our findings provide evidence for a superior effect of combined ET and testosterone replacement therapies on muscle sympathetic nerve activity, muscle wasting, and functional capacity in patients with HF with testosterone deficiency.

Iron complex with ionic tag-catalyzed olefin reduction under oxidative conditions--a different reaction for iron.

An iron(III) complex with ionic tags was applied to the reduction of alkenes in imidazolium-based ionic liquids (ILs) under oxidative conditions. The catalyst is very efficient to promote reactions of biomass derivatives. At least ten recycling reactions were performed without any loss of catalytic activity. Some important mechanistic insights for this new reaction are also provided based mostly on electrospray ionization quadrupole-time of flight mass spectrometry (ESI-QTOF-MS).

Mechanistic studies on Lewis acid catalyzed Biginelli reactions in ionic liquids: evidence for the reactive intermediates and the role of the reagents.

This paper describes the use of common Lewis acids supported in imidazolium-based ionic liquids as the catalysts to promote the Biginelli reaction. The ionic liquid effect and the reaction mechanism are discussed on the basis of nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), and theoretical calculations. Indeed, the results showed that the ionic medium plays a fundamental role in the synthesis of biologically active dihydropyrimidinones due to the stabilization of the charged intermediates proposed in the mechanism. When conducted in an ionic liquid as solvent, the reaction mechanism is more complex than in other Lewis acid catalyzed Biginelli reactions.

On the search for potential anti-Trypanosoma cruzi drugs: synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions.

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-ß-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC(50)/24h values in the range of 10.9-101.5 µM. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies.

Ionically tagged iron complex-catalyzed epoxidation of olefins in imidazolium-based ionic liquids.

A new ionophilic ligand and a new ionically tagged imidazolium-based iron(III) complex were synthesized and applied in the air oxidation (also hydrogen peroxide) of alkenes in imidazolium-based ionic liquids. At least ten recycling reactions were performed. The epoxidized olefin was obtained in very good yields of 84-91 %. Some important mechanistic insights are also provided based on electrospray ionization quadrupole-time of flight mass spectrometry for the oxidation reaction. These results indicate that oxidations can take place by two different pathways, depending on the reaction condition: a radical or a concerted mechanism. These results contribute towards a better understanding of iron-catalyzed oxidation mechanisms.

Charge-tagged acetate ligands as mass spectrometry probes for metal complexes investigations: applications in Suzuki and Heck phosphine-free reactions.

An acetate anion bearing an imidazolium cation as its charge tag was reacted with M(OAc)(2) complexes (where M = Ni, Cu, and Pd; in situ reaction) to form members of a new class of charge-tagged metal complexes. The formation of these unprecedented precatalysts with potential for cross-coupling reactions was confirmed by electrospray ionization (and tandem) mass spectrometry. The catalytic performance of the palladium complex was tested in Heck and Suzuki cross-coupling reactions, often with superior activity and yields as compared with Pd(OAc)(2).

Synthesis and evaluation of quinonoid compounds against tumor cell lines.

Thirty two compounds were synthesized in moderate to high yields and showed activity against cancer cells HL-60 (leukemia), MDA-MB435 (melanoma), HCT-8 (colon) and SF295 (central nervous system), with IC(50) below 2 µM for some compounds. The ß-lapachone-based 1,2,3-triazoles showed the best cytoxicity profile and emerge as promising anticancer prototypes. Insights about the reactive oxygen species (ROS) mechanism of anticancer action for some compounds were obtained by addition of 1-bromoheptane that deplete reduced glutathione (GSH) content and by using N-acetylcysteine that protects cells against apoptotic cellular death, as well by analysis of thiobarbituric acid reactive substances (TBARS) formation, and oxidative DNA damage after treatment detected by the comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII).

Glu298Asp eNOS gene polymorphism causes attenuation in nonexercising muscle vasodilatation.

The influence of Glu298Asp endothelial nitric oxide synthase (eNOS) polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that nonexercising forearm blood flow (FBF) responses during handgrip isometric exercise would be attenuated in individuals carrying the Asp298 allele. In addition, these responses would be mediated by reduced eNOS function and NO-mediated vasodilatation or sympathetic vasoconstriction. From 287 volunteers previously genotyped, we selected 33 healthy individuals to represent three genotypes: Glu/Glu [n = 15, age 43 +/- 3 yr, body mass index (BMI) 22.9 +/- 0.3 kg/m(2)], Glu/Asp (n = 9, age 41 +/- 3 yr, BMI 23.7 +/- 1.0 kg/m(2)), and Asp/Asp (n = 9, age 40 +/- 4 yr, BMI 23.5 +/- 0.9 kg/m(2)). Heart rate (HR), mean blood pressure (MBP), and FBF (plethysmography) were recorded for 3 min at baseline and 3 min during isometric handgrip exercise. Baseline HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among genotypes. FVC responses to exercise were significantly lower in Asp/Asp when compared with Glu/Asp and Glu/Glu (Delta = 0.07 +/- 0.14 vs. 0.64 +/- 0.20 and 0.57 +/- 0.09 units, respectively; P = 0.002). Further studies showed that intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA) did not change FVC responses to exercise in Asp/Asp, but significantly reduced FVC in Glu/Glu (Delta = 0.79 +/- 0.14 vs. 0.14 +/- 0.09 units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed (P = 0.62). l-NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp (P = 0.43). MBP and muscle sympathetic nerve activity increased significant and similarly throughout experimental protocols in Glu/Glu and Asp/Asp. Individuals who are homozygous for the Asp298 allele of the eNOS enzyme have attenuated nonexercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction.