ascorbic-acid and Heart-Failure

Vitamin C (Vit C) is an ideal antioxidant as it is easily available, water soluble, very potent, least toxic, regenerates other antioxidants particularly Vit E, and acts as a cofactor for different enzymes. It has received much attention due to its ability in limiting reactive oxygen species, oxidative stress, and nitrosative stress, as well as it helps to maintain some of the normal metabolic functions of the cell. However, over 140 clinical trials using Vit C in different pathological conditions such as myocardial infarction, gastritis, diabetes, hypertension, stroke, and cancer have yielded inconsistent results. Such a divergence calls for new strategies to establish practical significance of Vit C in heart failure or even in its prevention. For a better understanding of Vit C functioning, it is important to revisit its transport across the cell membrane and subcellular interactions. In this review, we have highlighted some historical details of Vit C and its transporters in the heart with a particular focus on heart failure in cancer chemotherapy.

Topics: Antioxidants; Ascorbic Acid; Heart Failure; Humans; Oxidative Stress; Reactive Oxygen Species

High sodium, high glucose, and obesity are important risk factors for age-related diseases such as cardiovascular disease (CVDs), stroke, and cancer. Coupling factor 6 (CF6) is released from vascular endothelial cells and functions as a circulating peptide that inhibits prostacyclin and nitric oxide generation by intracellular acidosis. High glucose elevates CF6 by activation of protein kinase C and p38 mitogen-activated protein kinase, whereas CF6 causes type 2 diabetes mellitus, resulting in a high glucose vicious cycle. Low glucose increases inhibitory factor peptide 1, an endogenous inhibitor of CF6. High salt intake increases CF6 through nuclear factor κB signaling, whereas CF6 induces salt-sensitive hypertension and salt-induced congestive heart failure. Oral administration of vitamin C cancels salt-induced increase in CF6, and estrogen replacement leads to the delayed onset of CF6-induced salt-sensitive hypertension and the rescue from cardiac systolic dysfunction. Because CF6 contributes to the onset of CVDs, nutritional regulation of CF6 will shed light on the understanding of preventive strategy and mechanisms for CVDs and a target for therapy.

Topics: Administration, Oral; Ascorbic Acid; Diabetes Mellitus, Type 2; Endothelial Cells; Epoprostenol; Heart Failure; Humans; Hypertension; Mitochondrial Proton-Translocating ATPases; NF-kappa B; Nitric Oxide; Oxidative Phosphorylation Coupling Factors; p38 Mitogen-Activated Protein Kinases; Protein Kinase C; Signal Transduction; Sodium Chloride, Dietary

Physicians' use of micronutrients to improve symptoms or outcomes in chronic illness has until recently been guided by limited data on the actions of individual agents in vitro or in animal studies. However several recently published clinical trials have provided information about which groups of patients are likely to benefit from which combination of micronutrients. Patients with chronic cardiac failure (CCF), particularly elderly individuals, have several reasons to be deficient in micronutrients including reduced intake, impaired gastrointestinal absorption and increased losses on the background of increased utilisation due for example to increased oxidative stress. Studies of nutritional supplementation in CCF patients have usually concentrated on specific agents. However given that many micronutrients have synergistic influences upon metabolic processes this strategy might merely lead to a shifting of a limiting step. Rather, a strategy of increasing the availability of multiple agents at once might be more logical. The aim of this article is to briefly review the experimental rationale for each of the micronutrients of potential benefit in chronic heart failure and examine the current clinical trial evidence supporting their use.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium; Carnitine; Copper; Dietary Supplements; Heart Failure; Humans; Magnesium; Magnesium Deficiency; Micronutrients; Niacin; Oxidative Stress; Phosphocreatine; Ubiquinone; Vitamin B Complex; Vitamin B Deficiency; Vitamin E; Zinc

Topics: Animals; Antioxidants; Ascorbic Acid; Chronic Disease; Endothelium, Vascular; Free Radicals; Heart Failure; Humans; Hypertension; Nitric Oxide; Renin-Angiotensin System

Topics: Antioxidants; Ascorbic Acid; Coronary Disease; Drug Tolerance; Free Radicals; Heart Failure; Humans; Muscle, Smooth, Vascular; Nitrates; Reactive Oxygen Species; Vitamin E

Topics: Adolescent; Arrhythmias, Cardiac; Ascorbic Acid; Blood Transfusion; Child; Cholelithiasis; Deferoxamine; Endocrine System Diseases; Female; Folic Acid; Growth Disorders; Heart Failure; Hematopoiesis; Humans; Iron; Leg Ulcer; Liver Diseases; Male; Pericarditis; Splenectomy; Thalassemia; Vitamin E

This study sought to characterize the role of free radicals in regulating central and peripheral hemodynamics at rest and during exercise in patients with heart failure (HF). We examined cardiovascular responses to dynamic handgrip exercise (4, 8, and 12 kg at 1 Hz) following consumption of either a placebo or acute oral antioxidant cocktail (AOC) consisting of vitamin C, E, and α-lipoic acid in a balanced, crossover design. Central and peripheral hemodynamics, mean arterial pressure, cardiac index, systemic vascular resistance (SVR), brachial artery blood flow, and peripheral (arm) vascular resistance (PVR) were determined in 10 HF patients and 10 age-matched controls. Blood assays evaluated markers of oxidative stress and efficacy of the AOC. When compared with controls, patients with HF exhibited greater oxidative stress, measured by malondialdehyde (+36%), and evidence of endogenous antioxidant compensation, measured by greater superoxide dismutase activity (+83%). The AOC increased plasma ascorbate (+50%) in both the HF patients and controls, but significant systemic hemodynamic effects were only evident in the patients with HF, both at rest and throughout exercise. Specifically, the AOC reduced mean arterial pressure (-5%) and SVR (-12%) and increased cardiac index (+7%) at each workload. In contrast, peripherally, brachial artery blood flow and PVR (arm) were unchanged by the AOC. In conclusion, these data imply that SVR in patients with HF is, at least in part, mediated by oxidative stress. However, this finding does not appear to be the direct result of muscle-specific changes in PVR.

Topics: Administration, Oral; Antioxidants; Arterial Pressure; Ascorbic Acid; Biomarkers; Blood Flow Velocity; Brachial Artery; Cross-Over Studies; Exercise; Hand Strength; Heart Failure; Hemodynamics; Humans; Male; Malondialdehyde; Middle Aged; Muscle Contraction; Muscle, Skeletal; Oxidative Stress; Regional Blood Flow; Single-Blind Method; Superoxide Dismutase; Thioctic Acid; Time Factors; Ultrasonography, Doppler; Utah; Vascular Resistance; Vitamin E

The increased central sympathetic activity typically associated with chronic heart failure (CHF) is probably mediated by formation of reactive oxygen species (ROS) in the brain. Our objective was to undertake a trial to test our hypothesis that administration of the well-known antioxidant and ROS scavenger ascorbic acid, would reverse or reduce the sympathetic overactivity in CHF patients.. In a prospective, randomized, placebo-controlled, double-blind, cross-over trial, 11 CHF patients were treated with ascorbic acid 2 g/day or placebo for 3 days. At the end of each treatment period, sympathetic nervous system activity was measured by microneurography for direct muscle sympathetic nerve activity (MSNA) recording, analysis of heart rate variability (HRV) and measurement of plasma norepinephrine concentrations.. During ascorbic acid administration, plasma vitamin C levels were higher than during placebo (74·9 ± 6·0 μmol/L vs. 54·8 ± 4·6 μmol/L, P = 0·03). Ascorbic acid had no effect on sympathetic activity: MSNA (ascorbic acid: 66·8 ± 3·3 vs. placebo 66·9 ± 3·2 bursts/100 beats, P = 0·98). In addition, HRV and plasma norepinephrine levels did not differ..   Short-term administration of the antioxidant ascorbic acid in CHF patients does not reverse the increased sympathetic activity as measured by microneurography, HRV and plasma norepinephrine levels. The use of higher oral dosages seems not feasible due to accompanying side effects.

Topics: Aged; Ascorbic Acid; Blood Pressure; Chronic Disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Free Radical Scavengers; Heart Failure; Heart Rate; Humans; Male; Microelectrodes; Middle Aged; Muscles; Norepinephrine; Placebos; Prospective Studies; Reactive Oxygen Species; Sample Size; Sympathetic Nervous System

1. It has recently been shown that oxidative stress is involved in the pathogenesis of congestive heart failure (CHF) in broiler chickens. Vitamins E and C, common antioxidants, have been advocated for the prevention of heart failure in humans. The present study examines the effects of supplementation of these vitamins on incidence of CHF and prevention of oxidative stress in the myocardium. 2. Commercial male broilers were randomly allocated to three experimental groups and, respectively, offered commercial broiler diet (control), commercial diets fortified with vitamin E (960 IU/kg) or vitamin C (400 mg/kg). The broilers were monitored daily for overt signs of heart failure and clinical data including ECG and blood gas analysis were collected periodically. Lipid peroxidation was measured in cardiac tissues from apparently normal broilers and broilers developing CHF in each group using thiobarbituric acid reactive substances (TBARS) assay. 3. Overall, the incidence of CHF in broilers given diets fortified with vitamin E or vitamin C was not significantly different as compared to the control group. The incidence of overt signs of hypoxaemia was lower in the vitamin C group than in the control group. Lipid peroxidation was highest in broilers that developed CHF as compared to apparently normal broilers fed either vitamin E or C fortified diets. Neither vitamin E nor vitamin C was effective in preventing oxidative damage in broilers that developed CHF. 4. In conclusion, the present study confirmed that oxidative stress is involved in the pathogenesis of heart failure in broilers, but dietary supplementation of antioxidant vitamins did not prevent oxidative damage in broilers that developed CHF. Beneficial effects of vitamin C supplementation were evidenced by lower incidence of hypoxaemia, and the tendency to reduce the susceptibility of broilers to heart failure. However, vitamin E did not have any impact on clinical status or the incidence of CHF.

Topics: Animals; Ascorbic Acid; Blood Gas Analysis; Chickens; Dietary Supplements; Electrocardiography; Heart Failure; Lipid Peroxidation; Male; Myocardium; Oxidative Stress; Poultry Diseases; Vitamin E; Vitamins

Aminothiols have a critical function as intracellular redox buffers and constitute furthermore an important extracellular redox system. Lipid peroxidation is increased in chronic heart failure (CHF), but the contribution of each thiol to oxidative stress in this syndrome has not been evaluated.. To assess the correlation between blood and plasma concentrations of aminothiols and lipid peroxidation as marker of oxidative stress in CHF patients.. Blood reduced glutathione (GSH), plasma total and reduced cysteine, cysteinylglycine, homocysteine, GSH, alpha-tocopherol, ascorbic acid, and free malondialdehyde (MDA) were assessed in samples obtained from 26 CHF heart transplant candidates and 26 age- and gender-matched controls with atherosclerotic risk factors and no history of cardiovascular disease. Results are expressed as median and interquartile range (I-III).. MDA levels were significantly higher in CHF patients than in controls [1.03 (0.56-1.60) microM vs. 0.70 (0.40-0.83) microM, p=0.006]. Blood reduced GSH concentrations were significantly higher [662 (327-867) microM vs. 416 (248-571) microM, p=0.016], while alpha-tocopherol levels were significantly lower [15 (13-19) microM vs. 21 (17-32) microM, p=0.001] in CHF patients than in controls. By multivariate logistic regression analysis, the only independent predictors of lipid peroxidation, as expressed by MDA levels > or = 1.00 microM, were increased blood GSH concentrations (OR 1.003 per unit, 95% CI 1.001 to 1.006, p=0.008), ischemic (OR 20, 95% CI 2.6 to 155, p=0.004) and non ischemic CHF etiology (OR 11, 95% CI 1.3 to 99, p=0.026).. Abnormalities in intracellular GSH cycling are associated to increased lipid peroxidation in CHF.

Topics: Adult; alpha-Tocopherol; Ascorbic Acid; Biomarkers; Female; Glutathione; Heart Failure; Humans; Lipid Peroxidation; Logistic Models; Male; Malondialdehyde; Middle Aged; Multivariate Analysis; Risk Factors

Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction.. We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism.. We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study.. Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05).. These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

Topics: Adenosine Triphosphate; Aged; Ascorbic Acid; Chronic Disease; Double-Blind Method; Endothelium, Vascular; Female; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; United Kingdom

Endothelial dysfunction is an early event in the natural progression of heart failure. Increased oxidative stress has been linked to impaired endothelial function and both may play a prognostic role.. Endothelium-dependent and endothelium-independent vasodilatation were determined in 289 patients with mild left ventricular dysfunction by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. Vascular effects of the coadministration of the antioxidant vitamin C at pharmacological doses (24 mg/min) were assessed. Occurrence of death, heart transplantation, and readmission with worsening heart failure were recorded as clinical outcome parameters during a follow-up period of 4.8 years. Patients experiencing adverse events (n=79) had lower vasodilator responses to acetylcholine (P<0.001) and to sodium nitroprusside (P=0.03) compared with patients without events. However, beneficial effects of vitamin C did not differ between both groups. Cox proportional hazards model demonstrated that age (P=0.001), renal function (P=0.001), and blunted acetylcholine-induced vasodilatation (P=0.007) remained independent predictors of adverse outcome.. Impaired peripheral endothelial function independently predicts long-term adverse outcome in patients with early-stage heart failure. The findings suggest that assessment of peripheral endothelial function may represent an additional mean for risk stratification and therapy management in these patients.

Topics: Acetylcholine; Aged; Antioxidants; Ascorbic Acid; Diagnostic Techniques, Cardiovascular; Disease-Free Survival; Endothelium, Vascular; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Nitroprusside; Oxidative Stress; Predictive Value of Tests; Prognosis; Prospective Studies; Regional Blood Flow; Risk Factors; Vasodilation; Vasodilator Agents

The positive effect of vitamin C on left ventricular (LV) inotropic responses to dobutamine, observed in patients with preserved LV function, is lost in heart failure (HF). We tested the hypothesis that in HF, endogenous nitric oxide (NO) opposes the positive effect of vitamin C on adrenergically stimulated contractility by examining the effects of vitamin C on dobutamine responses during NO synthase inhibition. In 11 HF patients, a micromanometer-tipped catheter was inserted into the LV and an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary N(G)-monomethyl-L-arginine (l-NMMA) was infused before reinfusion of dobutamine (L-NMMA + Dob-2). Finally, intracoronary vitamin C was infused in addition to intracoronary L-NMMA and dobutamine (L-NMMA + Dob-2 + vitamin C). Intracoronary L-NMMA alone had no effect on LV +dP/dt. After a stable inotropic response to intracoronary L-NMMA and dobutamine was established, the addition of intracoronary vitamin C resulted in a modest but significant increase in LV +dP/dt. The change in LV +dP/dt in response to dobutamine alone was 25 +/- 5%, with intracoronary L-NMMA, 27 +/- 6%, and with intracoronary L-NMMA plus vitamin C, 37 +/- 5% (P < 0.05 vs. Dob-1 and L-NMMA + Dob-2). These findings demonstrate that an interaction between endogenous NO and redox environment exists and exerts some influence on stimulated contractility in HF.

Topics: Ascorbic Acid; Blood Pressure; Cardiotonic Agents; Dobutamine; Drug Combinations; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Myocardial Contraction; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Treatment Outcome; Ventricular Dysfunction, Left

The significance of antioxidant therapy in heart failure has not been fully examined. This study evaluated whether vitamin C has beneficial effects on renal function or augments the renal effects of furosemide in patients with heart failure.. There were 2 protocols. In protocol 1, plasma level of thiobarbituric acid-reactive substances (TBARS) and renal function were assessed before and after intravenous infusion of vitamin C or placebo in 8 patients with moderate congestive heart failure (CHF) treated with enalapril. In protocol 2, a randomized crossover study was performed in patients with moderate CHF treated with either an ACE inhibitor (enalapril) (n = 10) or an angiotensin II receptor antagonist (losartan) (n = 9) and in asymptomatic patients with impaired left ventricular function treated with enalapril (n = 8). TBARS and renal function were assessed before and after intravenous infusion of furosemide alone, coinfusion of furosemide with placebo and vitamin C, or coinfusion of furosemide with vitamin C and a kallikrein inhibitor (nafamostat mesilate).. In protocol 1, although vitamin C reduced TBARS, it did not affect renal function. In protocol 2, TBARS was higher in patients with moderate CHF than in asymptomatic patients. Vitamin C augmented natriuretic effect of furosemide (from 179 +/- 98 to 192 +/- 104 micromol/min, P <.01) only in patients with moderate CHF treated with enalapril but not in the other 2 groups. Nafamostat mesilate prevented this augmentation.. In patients with CHF treated with enalapril, counteraction of the increased oxidative stress by vitamin C may contribute to the augmented natriuretic effect of furosemide through the renal kinin-nitric oxide pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid; Cross-Over Studies; Cyclic GMP; Drug Therapy, Combination; Enalapril; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Oxidative Stress

Abnormalities of autonomic control of the cardiovascular system are seen in chronic heart failure (CHF) and confer a poor prognosis. Nitric oxide appears to be important in the regulation of baroreflex control in health and in disease states. The antioxidant vitamin C increases nitric oxide bioavailability in CHF. We evaluated the effects of vitamin C on baroreceptor sensitivity (BRS) by sequence analysis in 100 CHF patients and 44 control subjects. Groups of 55 CHF patients and 22 controls were randomly allocated to receive a single intravenous injection of vitamin C (2 g) or placebo. In addition, 45 CHF patients were randomly allocated to receive a 4-week course of oral vitamin C (4 g/day) or placebo. An age-related reference range for BRS was developed in 22 healthy controls matched for age and gender to the CHF group. BRS was significantly impaired in the CHF group compared with age-matched older controls and young controls (6.9 +/- 3.1, 12.5 +/- 4.9 and 21.7 +/- 9.1 mmHg/ms respectively; P < 0.001 between groups). Intravenous vitamin C acutely improved BRS in CHF patients by 24% (by 1.8 +/- 4.1 mmHg/ms; P < 0.05), but not in controls. There was no improvement in BRS in CHF patients given chronic oral vitamin C. Thus acute intravenous, but not chronic oral, vitamin C improved BRS in CHF patients. There was no effect of intravenous vitamin C in healthy subjects, suggesting that the mechanism was either by free radical scavenging or due to central effects.

Topics: Administration, Oral; Adult; Aged; Ascorbic Acid; Baroreflex; Blood Flow Velocity; Case-Control Studies; Female; Heart Failure; Humans; Injections, Intravenous; Male; Middle Aged; Multivariate Analysis; Nitric Oxide; Oxidative Stress; Pressoreceptors

Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM).. In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% +/- 3%), ICM (n = 9; LVEF, 25% +/- 4%), DCM (n = 9; LVEF, 25% +/- 3%), and healthy subjects (HS; n = 5; LVEF, 66% +/- 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 microg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min).. Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 +/- 20 microm; ICM, 86 +/- 20 microm) and patients with CAD (336 +/- 20 microm) as compared with HS (496 +/- 43 microm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 +/- 35 microm (to 270 +/- 30 microm) in DCM (P <.05 vs CAD, HS) and by 294 +/- 40 microm (to 380 +/- 20 microm) in ICM (P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 +/- 35 microm to normal values, whereas vascular diameter remained unchanged in HS (14 +/- 20 microm; P = not significant).. Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.

Topics: Acetylcholine; Aged; Ascorbic Acid; Cardiomyopathy, Dilated; Chronic Disease; Coronary Artery Disease; Drug Therapy, Combination; Endothelium, Vascular; Heart Failure; Humans; Male; Middle Aged; Myocardial Ischemia; Nitroprusside; Oxidative Stress; Vasodilation; Vasodilator Agents

Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in patients with chronic heart failure (CHF) results, at least in part, from accelerated degradation of nitric oxide by oxygen radicals. The mechanisms leading to increased vascular radical formation, however, remain unclear. Therefore, we determined endothelium-bound activities of extracellular superoxide dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a potent radical producing enzyme, and their relation to FDD in patients with CHF.. ecSOD and xanthine-oxidase activities, released from endothelium into plasma by heparin bolus injection, were determined in 14 patients with CHF and 10 control subjects. FDD of the radial artery was measured using high-resolution ultrasound and was assessed before and after administration of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium-bound ecSOD activity was substantially reduced (5.0+/-0.7 versus 14.4+/-2.6 U x mL(-1) x min(-1); P<0.01) and closely related to FDD (r=0.61). Endothelium-bound xanthine-oxidase activity was increased by >200% (38+/-10 versus 12+/-4 nmol O2*- x microL(-1); P<0.05) and inversely related to FDD (r=-0.35) in patients with CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by radicals correlated negatively with ecSOD (r=-0.71) but positively with xanthine-oxidase (r=0.75).. These results demonstrate that both increased xanthine-oxidase and reduced ecSOD activity are closely associated with increased vascular oxidative stress in patients with CHF. This loss of vascular oxidative balance likely represents a novel mechanism contributing to endothelial dysfunction in CHF.

Topics: Antioxidants; Ascorbic Acid; Chronic Disease; Endothelium, Vascular; Enzyme Activation; Extracellular Space; Female; Free Radicals; Heart Failure; Humans; Male; Middle Aged; Oxidative Stress; Radial Artery; Regional Blood Flow; Superoxide Dismutase; Ultrasonography; Vasodilation; Xanthine Oxidase

Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.

Topics: Adult; Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Chronic Disease; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Female; Heart Failure; Humans; Linear Models; Male; Middle Aged; Nitric Oxide Donors; Nitroglycerin; Nitroprusside; Oxidative Stress; Platelet Aggregation; Vasodilator Agents

Proinflammatory cytokines like tumor necrosis factor-alpha and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients.. Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor-alpha and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32+/-8% of baseline levels, whereas placebo had no effect (87+/-14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001).. Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function.

Topics: Administration, Oral; Adult; Aged; Angiotensin II; Apoptosis; Ascorbic Acid; Biomarkers; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium, Vascular; Enzyme Inhibitors; Female; Heart Failure; Humans; Injections, Intravenous; Male; Middle Aged; Oxidative Stress; Prospective Studies; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF.. Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven.. We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O2-) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF.. At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O2- -generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O2- -generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O2- -generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress.. Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O2- generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.

Topics: Anions; Ascorbic Acid; Chronic Disease; Endothelium; Female; Heart Failure; Humans; Male; Neutrophils; Oxidative Stress; Superoxides; Time Factors

Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.. Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 microg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (micromol/L), and platelet cGMP level (pmol/10[9] platelets) were comparable in the two groups (placebo group: MPAP, 48+/-6; PCWP, 24+/-4; cGMP, 0.76+/-0.12; vitamin E, 18.2+/-1.2; vitamin C: MPAP, 49+/-7; PCWP, 24+/-4; cGMP, 0.71+/-0.16; vitamin E, 18.6+/-1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26+/-5; PCWP, 15+/-4; vitamin C: MPAP, 26+/-4; PCWP, 16+/-4), and platelet cGMP was significantly increased (placebo group: 2.42+/-0.24; vitamin C: 2.26+/-0.26). However, at 18 hours after titration, in the placebo group, MPAP (44+/-5) and PCWP (23+/-4) were increased, and platelet cGMP (0.85+/-0.20) and plasma vitamin E levels (12.4+/-1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31+/-6), PCWP (17+/-5), platelet cGMP (2.49+/-0.23), and plasma vitamin E levels (17.6+/-1.4) were maintained for 18 hours after the titration period.. These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

Topics: Aged; Ascorbic Acid; Blood Platelets; Blood Pressure; Cyclic GMP; Double-Blind Method; Drug Tolerance; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Nitroglycerin; Vitamin E

What is the central question of this study? We aimed to examine oxidative stress, antioxidant capacity and macro- and microvascular function in response to 30 days of oral antioxidant administration in patients with heart failure with reduced ejection fraction. What is the main finding and its importance? We observed an approximately twofold improvement in macrovascular function, assessed via brachial artery flow-mediated dilatation, and a reduction in oxidative stress after antioxidant administration in patients with heart failure with reduced ejection fraction. The improvement in macrovascular function was reversed 1 week after treatment cessation. These findings have identified the potential of oral antioxidant administration to optimize macrovascular health in this patient group.. Heart failure with reduced ejection fraction (HFrEF) is characterized by macrovascular dysfunction and elevated oxidative stress that may be mitigated by antioxidant (AOx) administration. In this prospective study, we assessed flow-mediated dilatation (FMD) and reactive hyperaemia responses in 14 healthy, older control participants and 14 patients with HFrEF, followed by 30 days of oral AOx administration (1 g vitamin C, 600 I.U. vitamin E and 0.6 g α-lipoic acid) in the patient group. Blood biomarkers of oxidative stress (malondialdehyde) and AOx capacity (ferric reducing ability of plasma) were also assessed. Patients with HFrEF had a lower %FMD (2.63 ± 1.57%) than control participants (5.62 ± 2.60%), and AOx administration improved %FMD in patients with HFrEF (30 days, 4.90 ± 2.38%), effectively restoring macrovascular function to that of control participants. In a subset of patients, we observed a progressive improvement in %FMD across the treatment period (2.62 ± 1.62, 4.23 ± 2.69, 4.33 ± 2.24 and 4.97 ± 2.56% at days 0, 10, 20 and 30, respectively, n = 12) that was abolished 7 days after treatment cessation (2.99 ± 1.78%, n = 9). No difference in reactive hyperaemia was evident between groups or as a consequence of the AOx treatment. Ferric reducing ability of plasma levels increased (from 6.08 ± 2.80 to 6.70 ± 1.59 mm, day 0 versus 30) and malondialdehyde levels decreased (from 6.81 ± 2.80 to 6.22 ± 2.84 μm, day 0 versus 30) after treatment. These findings demonstrate the efficacy of chronic AOx administration in attenuating oxidative stress, improving AOx capacity and restoring macrovascular function in patients with HFrEF.

Topics: Aged; Antioxidants; Ascorbic Acid; Biomarkers; Case-Control Studies; Female; Heart Failure; Humans; Hyperemia; Male; Middle Aged; Oxidative Stress; Prospective Studies; Thioctic Acid; Ventricular Dysfunction, Left; Vitamin E

Although it is now well established that heart failure with preserved ejection fraction (HFpEF) is associated with marked inflammation and a prooxidant state that is accompanied by vascular dysfunction, whether acute antioxidant (AO) administration can effectively target these disease-related decrements has not been evaluated. Thus, the present study sought to evaluate the efficacy of an acute over-the-counter AO cocktail (600 mg α-lipoic acid, 1,000 mg vitamin C, and 600 IU vitamin E) to mitigate inflammation and oxidative stress, and subsequently improve nitric oxide (NO) bioavailability and vascular function, in patients with HFpEF. Flow-mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, 90 min after administration of either placebo (PL) or AO in 16 patients with HFpEF (73 ± 10 yr, EF 54-70%) using a double-blind, crossover design. Circulating biomarkers of inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde and protein carbonyl), free radical concentration (EPR spectroscopy), antioxidant capacity, ascorbate and NO bioavailability (plasma nitrate, [Formula: see text], and nitrite, [Formula: see text]) were also assessed. FMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), whereas RH responses were similar between conditions (PL: 428 ± 51 mL, AO: 425 ± 51 mL). AO administration decreased CRP (PL: 4,429 ± 705 ng/mL, AO: 3,664 ± 520 ng/mL) and increased ascorbate (PL: 30.0 ± 2.9 µg/mL, AO: 45.1 ± 3.7 µg/mL) and [Formula: see text] (PL: 182 ± 21 nM, AO: 213 ± 24 nM) but did not affect other biomarkers. Together, these data suggest that acute AO administration can exert anti-inflammatory effects and improve conduit artery vasodilation, but not microvascular function, in patients with HFpEF.

Topics: Antioxidants; Ascorbic Acid; Endothelium, Vascular; Heart Failure; Humans; Hyperemia; Inflammation; Oxidative Stress; Stroke Volume; Ventricular Function, Left; Vitamin E

A family of 12 members of Naphthalene-2-ol-indolin-2-one-thiocarbamides (5a-l) with pharmacological potentials of cardiovascular modulator were efficiently synthesized and evaluated. These compounds show inhibitory activity on angiotensin-converting enzyme (ACE), which is a principal constituent of the renin-angiotensin system and causative source for hypertension (HTN) (elevated blood pressure) and congestive heart failure (CHF), a parameter that was tested in this report. Prior to this, to get more insight into the binding mode and inhibition of human ACE C-domain (PDB ID: 2XY9) and N-domain (PDB ID: 3NXQ) compounds 5a-l was docked into the active site of them. The established inhibitory constant (Ki) (range 40-500 nM) and least binding affinities (-18.52 to -30.57 kcal/mol) indicated the therapeutic selectivity of compounds 5a-l towards ACE C-domain inhibition over ACE N-domain. The cytotoxicity effect of most potent compounds among 5a-l were tested in normal breast cells and MCF-7 cell lines. Simultaneously, H

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Heart Failure; Humans; Hypertension; Indoles; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Thrombolytic Therapy

The oxidative stress of placenta during fetal heart dysfunction (FHD) is lack of evaluation. So, we carried out an experiment to explore whether vitamin C (VitC) can be supplied for placental protection under FHD and its impacts on P-glycoprotein expression.. Fetal heart dysfunction was induced by two intra-amniotic injections of isoproterenol, then (VitC) was supplied. Hematoxylin-eosin (HE) staining was used to evaluate placental histology, and oxidative stress was measured by total antioxidant capacity, total superoxide dismutase and level of advanced oxidation protein products (AOPP), as well as apoptosis rate. Real-time polymerase chain reaction was adopted to measure the expressions of superoxide dismutase-1 (Sod-1), glutathione peroxidase-1 (Gpx-1) and endothelial nitric oxide synthase (eNOS) in placenta. Finally, western blot was performed to detect P-glycoprotein expression.. All isoproterenol twice-treated fetuses exhibited significant (P < 0.05) contractile dysfunction by fetal echocardiography compared to others. The HE staining showed severe placental hydrops in the FHD group, and that hydrops could be reduced by VitC treatment. Total antioxidant capacity and total Sod-1 decreased in FHD and elevated after VitC supplementation. Also, level of AOPP increased in FHD and dropped after VitC supplementation. Analysis of apoptosis demonstrated that there was a mild increase in apoptosis rate of FHD. Reductions of Sod-1 and eNOS mRNA expression were confirmed in FHD, but these could recovered after VitC supplementation, with the same tendency of the P-glycoprotein.. Severe oxidative injuries were identified in placentas of FHD with P-glycoprotein repression. VitC administration can reduce the oxidative stress and rebuild the protective mechanism of placenta.

Topics: Animals; Antioxidants; Ascorbic Acid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Models, Animal; Echocardiography; Female; Fetal Diseases; Heart Failure; Oxidative Stress; Placenta; Placenta Diseases; Polymerase Chain Reaction; Pregnancy; Rats, Sprague-Dawley

Ageing is an important risk factor of cardiovascular diseases including heart failure. Senescence marker protein 30 (SMP30), which was originally identified as an important ageing marker protein, is assumed to act as a novel anti-ageing factor in various organs. However, the role of SMP30 in the heart has not been previously explored. In this study, our aim was to elucidate the functional role of SMP30 on cardiac remodelling.. SMP30 knockout (KO) mice and wild-type (WT) mice were subjected to continuous angiotensin II (Ang II) infusion. After 14 days, the extent of cardiac hypertrophy and myocardial fibrosis was significantly higher in SMP30-KO mice than in WT mice. Echocardiography revealed that SMP30-KO mice had more severely depressed systolic and diastolic function with left ventricular dilatation compared with WT mice. Generation of reactive oxygen species related with activation of nicotinamide adenine dinucleotide phosphate-oxidase was greater in SMP30-KO mice than in WT mice. The number of deoxynucleotidyl transferase-mediated dUTP nick end-labelling positive nuclei was markedly increased in SMP30-KO mice with activation of caspase-3, increases in the Bax to Bcl-2 ratio and phosphorylation of c-Jun N-terminal kinase compared with WT mice. Furthermore, the number of senescence-associated β-galactosidase-positive cells was significantly increased via up-regulation of p21 gene expression in SMP30-KO mice compared with WT mice.. This study demonstrated the first evidence that deficiency of SMP30 exacerbates Ang II-induced cardiac hypertrophy, dysfunction, and remodelling, suggesting that SMP30 has a cardio-protective role in cardiac remodelling with anti-oxidative and anti-apoptotic effects in response to Ang II.

Topics: Aging; Angiotensin II; Animals; Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Biomarkers; Calcium-Binding Proteins; Cardiomegaly; Caspase 3; Disease Models, Animal; Fibrosis; Heart Failure; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Ventricular Remodeling

Oxidative stress has been implicated in the pathogenesis of heart failure (HF). However, data on the association between antioxidant intakes and circulating levels and risk of incident HF in the older general population are limited. We have examined prospectively the associations between plasma vitamin C and E, dietary intakes of vitamin C and E, and incident HF.. Prospective study of 3919 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 11 years, in whom there were 263 cases with incident HF. Higher plasma vitamin C level was associated with significantly lower risk of incident HF in both men with and without previous myocardial infarction after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, and heart rate (hazards ratio [95% confidence interval], 0.81 [0.70, 0.93] and 0.75 [0.59, 0.97] for 1 SD increase in log vitamin C, respectively). Plasma vitamin E and dietary vitamin C intake showed no association with HF. High levels of dietary vitamin E intake (which correlated weakly with plasma vitamin E) were associated with increased risk of HF in men with no previous myocardial infarction even after adjustment (adjusted hazards ratio [95% confidence interval], 1.23 [1.06, 1.42] for 1 SD increase).. Higher plasma vitamin C is associated with a reduced risk of HF in older men with and without myocardial infarction. High intake of dietary vitamin E may be associated with increased HF risk. Primary intervention trials assessing the effect of vitamin C supplements on HF risk in the elderly are needed.

Topics: Aged; Ascorbic Acid; Diabetic Angiopathies; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Assessment; Vitamin E

Senescence marker protein 30 (SMP30), which was originally identified as an aging marker protein, is assumed to act as a novel anti-aging factor in the liver, lungs and brain. We hypothesized that SMP30 has cardio-protective function due to its anti-aging and anti-oxidant effects on doxorubicin (DOX)-induced cardiac dysfunction.. SMP30 knockout (SMP30 KO) mice, SMP30 transgenic (SMP30 TG) mice with cardiac-specific overexpression of SMP30 gene and wild-type (WT) littermate mice at 12-14 weeks of age were given intra-peritoneal injection of DOX (20 mg/kg) or saline. Five days after DOX injection, echocardiography revealed that left ventricular ejection fraction was more severely reduced in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but was preserved in the DOX-treated SMP30 TG mice. Generation of reactive oxygen species and oxidative DNA damage in the myocardium were greater in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but much less in the SMP30 TG mice. The numbers of deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive nuclei in the myocardium, apoptotic signaling pathways such as caspase-3 activity, Bax/Bcl-2 ratio and phosphorylation activity of c-Jun N-terminal kinase were increased in SMP30 KO mice and decreased in SMP30 TG mice compared with WT mice after DOX injection.. SMP30 has a cardio-protective role by anti-oxidative and anti-apoptotic effects in DOX-induced cardiotoxicity, and can be a new therapeutic target to prevent DOX-induced heart failure.

Topics: Aging; Animals; Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Biomarkers; Calcium-Binding Proteins; Cardiotonic Agents; Caspase 3; DNA Damage; Doxorubicin; Fibrosis; Heart Failure; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; Stroke Volume; Up-Regulation

Using flow-mediated vasodilation (FMD), reactive hyperemia, and an acute oral antioxidant cocktail (AOC; vitamins C and E and α-lipoic acid), this study aimed to provide greater insight into altered vascular function and the role of oxidative stress in chronic heart failure patients with reduced ejection fraction (HFrEF) and at several time points beyond heart transplantation (HTx). A total of 61 age-matched subjects (12 healthy controls, 14 New York Heart Association class II and III HFrEF, and 35 HTx recipients [<3 years post-HTx, 5-10 years post-HTx, and >14 years post-HTx]) ingested either placebo (PL) or an AOC before FMD and reactive hyperemia testing of the brachial artery. Vascular function, as measured by FMD, was not different among the controls (6.8±1.9%), recent <3-year post-HTx group (8.1±1.2%), and the 5- to 10-year post-HTx group (5.5±1.0%). However, PL FMD was lower in the HFrEF (4.5±0.7%) and in the >14-year post-HTx group (2.9±0.8%). The AOC increased plasma ascorbate levels in all of the groups but only increased FMD in the controls (PL, 6.8±1.9%; AOC, 9.2±1.0%) and >14-year post-HTx recipients (PL, 2.9±0.8%; AOC, 4.5±1.3%). There were no differences in reactive hyperemia in any of the groups with PL or AOC. This cross-sectional study reveals that, compared with controls, vascular function is blunted in HFrEF, is similar soon after HTx, but is decreased with greater time post-HTx with free radicals implicated in this progression.

Topics: Aged; Antioxidants; Ascorbic Acid; Brachial Artery; Case-Control Studies; Cross-Sectional Studies; Disease Progression; Female; Heart Failure; Heart Transplantation; Humans; Hyperemia; Male; Middle Aged; Oxidative Stress; Stroke Volume; Thioctic Acid; Vasodilation; Vitamin E

We describe the case of a 40-year-old female patient who developed severe pulmonary hypertension and life-threatening right-sided heart failure in association with dietary scurvy and iron deficiency. Supplementation with oral vitamin C and iron very likely contributed to her complete cure. Scurvy-associated pulmonary arterial hypertension could result from impaired availability of endothelial nitric oxide, but inappropriate activation of the hypoxia-inducible family (HIF) of transcription factors could play an even more important role. HIF coordinates the body's responses to hypoxia, and its activity is regulated by oxygen-dependent prolyl hydroxylases, which need vitamin C and iron as cofactors. Deficiency of these cofactors could lead to uncontrolled HIF activity and pulmonary vasoconstriction responsive to vitamin C and iron administration.

Topics: Adult; Anemia, Iron-Deficiency; Ascorbic Acid; Ascorbic Acid Deficiency; Dietary Supplements; Echocardiography; Female; Heart Failure; Humans; Hypertension, Pulmonary; Iron; Scurvy; Treatment Outcome; Vasoconstriction

We described recently that systemic hypoxia provokes vasoconstriction in heart failure (HF) patients. We hypothesized that either the exaggerated muscle sympathetic nerve activity and/or endothelial dysfunction mediate the blunted vasodilatation during hypoxia in HF patients. Twenty-seven HF patients and 23 age-matched controls were studied. Muscle sympathetic nerve activity was assessed by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. Peripheral chemoreflex control was evaluated through the inhaling of a hypoxic gas mixture (10% O(2) and 90% N(2)). Basal muscle sympathetic nerve activity was greater and basal FBF was lower in HF patients versus controls. During hypoxia, muscle sympathetic nerve activity responses were greater in HF patients, and forearm vasodilatation in HF was blunted versus controls. Phentolamine increased FBF responses in both groups, but the increase was lower in HF patients. Phentolamine and N(G)-monomethyl-l-arginine infusion did not change FBF responses in HF but markedly blunted the vasodilatation in controls. FBF responses to hypoxia in the presence of vitamin C were unchanged and remained lower in HF patients versus controls. In conclusion, muscle vasoconstriction in response to hypoxia in HF patients is attributed to exaggerated reflex sympathetic nerve activation and blunted endothelial function (NO activity). We were unable to identify a role for oxidative stress in these studies.

Topics: Adult; Ascorbic Acid; Case-Control Studies; Chemoreceptor Cells; Forearm; Heart Failure; Hemodynamics; Humans; Hypoxia; Middle Aged; Muscle, Smooth, Vascular; omega-N-Methylarginine; Oxidative Stress; Phentolamine; Regional Blood Flow; Sympathetic Nervous System; Vasoconstriction; Vasodilation

Fruit and vegetable intake has been associated with lower risk for cardiovascular risk factors and disease, but data on heart failure are sparse and inconsistent. The association of plasma vitamin C, a biomarker reflecting fruit and vegetable intake, with heart failure has not been studied.. We examined the prospective association of plasma vitamin C concentrations with incident fatal and nonfatal heart failure events in apparently healthy 9,187 men and 11,112 women aged 39 to 79 years participating in the "European Prospective Investigation into Cancer and Nutrition" study in Norfolk.. The risk of heart failure decreased with increasing plasma vitamin C; the hazard ratios comparing each quartile with the lowest were 0.76 (95% CI 0.65-0.88), 0.70 (95% CI 0.60-0.81), and 0.62 (95% CI 0.53-0.74) in age- and sex-adjusted analyses (P for trend <.0001). Every 20 μmol/L increase in plasma vitamin C concentration (1 SD) was associated with a 9% relative reduction in risk of heart failure after adjustment for age, sex, smoking, alcohol consumption, physical activity, occupational social class, educational level, systolic blood pressure, diabetes, cholesterol concentration, and body mass index, with similar result if adjusting for interim coronary heart disease.. Plasma vitamin C, a biomarker reflecting fruit and vegetable intake, was inversely associated with the risk of heart failure in this healthy population. This observation should be regarded as hypothesis generating for further prospective trials aimed at examining the effect of a diet rich in fruit and vegetables for prevention of heart failure.

Topics: Adult; Aged; Ascorbic Acid; Biomarkers; Diet Surveys; Disease Progression; Eating; Europe; Female; Follow-Up Studies; Fruit; Heart Failure; Humans; Incidence; Life Style; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Surveys and Questionnaires; Vegetables

Underlying cardiovascular disease (CVD) is a risk factor for the exacerbation of air pollution health effects. Pulmonary oxidative stress, inflammation, and altered iron (Fe) homeostasis secondary to CVD may influence mammalian susceptibility to air pollutants. Rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Baseline cardiac and pulmonary disease was characterized in healthy normotensive Wistar Kyoto (WKY) rats, cardiovascular compromised spontaneously hypertensive rats (SHR), and spontaneously hypertensive heart failure (SHHF) rats. Blood pressure, heart rate, and breathing frequencies were measured in rats 11 to 12 wk of age, followed by necropsy at 14 to 15 wk of age. Blood pressure and heart rate were increased in SHR and SHHF relative to WKY rats (SHR > SHHF > WKY). Increased breathing frequency in SHHF and SHR (SHR > SHHF > WKY) resulted in greater minute volume relative to WKY. Bronchoalveolar lavage fluid (BALF) protein and neutrophils were higher in SHHF and SHR relative to WKY (SHHF >> SHR > WKY). Lung ascorbate and glutathione levels were low in SHHF rats. BALF Fe-binding capacity was decreased in SHHF relative to WKY rats and was associated with increased transferrin (Trf) and ferritin. However, lung ferritin was lower and Trf was higher in SHHF relative to WKY or SHR rats. mRNA for markers of inflammation and oxidative stress (macrophage inflammatory protein [MIP]-2, interleukin [IL]-1alpha, and heme oxygenase [HO]-1) were greater in SHHF and SHR relative to WKY rats. Trf mRNA rose in SHR but not SHHF relative to WKY rats, whereas transferrin receptors 1 and 2 mRNA was lower in SHHF rats. Four of 12 WKY rats exhibited cardiac hypertrophy despite normal blood pressure, while demonstrating some of the pulmonary complications noted earlier. This study demonstrates that SHHF rats display greater underlying pulmonary complications such as oxidative stress, inflammation, and impaired Fe homeostasis than WKY or SHR rats, which may play a role in SHHF rats' increased susceptibility to air pollution.

Topics: Animals; Ascorbic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiovascular Diseases; Disease Models, Animal; Ferritins; Gene Expression; Glutathione; Heart Failure; Hemodynamics; Homeostasis; Hypertension; Inflammation; Iron; Lung; Lung Diseases; Male; Obesity; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Respiratory Function Tests; Stroke; Transferrin

The formation of reactive oxygen species (ROS) is increased in heart failure (HF). However, the causal and mechanistic relationship of ROS formation with contractile dysfunction is not clear in detail. Therefore, ROS formation, myofibrillar protein oxidation and p38 MAP kinase activation were related to contractile function in failing rabbit hearts.. Three weeks of rapid left ventricular (LV) pacing reduced LV shortening fraction (SF, echocardiography) from 32 +/- 1% to 13 +/- 1%. ROS formation, as assessed by dihydroethidine staining, increased by 36 +/- 8% and was associated with increased tropomyosin oxidation, as reflected by dimer formation (dimer to monomer ratio increased 2.28 +/- 0.66-fold in HF vs. sham, P < 0.05). Apoptosis (TdT-mediated dUTP nick end labelling staining) increased more than 12-fold after 3 weeks of pacing when a significant increase in the phosphorylation of p38 MAP kinase and HSP27 was detected (Western blotting). Vitamins C and E abolished the increases in ROS formation and tropomyosin oxidation along with an improvement of LVSF (19 +/- 1%, P < 0.05 vs. untreated HF) and prevention of apoptosis, but without modifying p38 MAP kinase activation. Inhibition of p38 MAP kinase by SB281832 counteracted ROS formation, tropomyosin oxidation and contractile failure, without affecting apoptosis.. Thus, p38 MAP kinase activation appears to be upstream rather than downstream of ROS, which impacts on LV function through myofibrillar oxidation. p38 MAP kinase inhibition is a potential target to prevent or treat HF.

Topics: Actin Cytoskeleton; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Heart Failure; Imidazoles; Male; Myocardial Contraction; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyrimidines; Rabbits; Reactive Oxygen Species; Ventricular Function, Left; Vitamin E

Indirect observations are compatible with cardiac vitamin C deficiency as one contributory factor to oxidative stress in heart failure, but data on ventricular vitamin C content are lacking. Here, we used the well established model of aortic-banded rats at the stage of compensated hypertrophy (6 weeks after banding) and at the transition to cardiac failure (22 weeks after banding) to analyze vitamin C, vitamin E, protein carbonyls and malondialdehyde tissue content together with the respective plasma concentrations. Furthermore, we investigated the expression of the vitamin C transporters SVCT1 and SVCT2 in the left ventricle (LV). Aortic-banded rats, independently from their age, had higher malondialdehyde and protein carbonyl levels in plasma and LV tissue compared to sham-operated animals indicating increased oxidative stress. Plasma vitamin C remained unaffected from cardiac overload, while LV vitamin C was elevated in both stages of hypertrophy together with an increased expression of the vitamin C transporter SVCT2 suggesting increased vitamin C uptake. The levels of antioxidants and lipid peroxides were similar 6 and 22 weeks after aortic banding. Therefore, the accumulation of vitamin C in compensated hypertrophy and in decompensated failure excludes cardiac vitamin C deficiency as a primary factor to oxidative stress in this model.

Topics: Animals; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Heart Failure; Hemodynamics; Hypertrophy, Left Ventricular; Lipid Peroxidation; Male; Malondialdehyde; Matrix Metalloproteinase 2; Myocardium; Organic Anion Transporters, Sodium-Dependent; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Coupled Vitamin C Transporters; Symporters; Tissue Inhibitor of Metalloproteinase-1; Vitamin E

Excessive oxidative stress is considered one of the mechanisms of a decrease in contractile force without concomitant reduction in oxygen cost in failing myocardium. We hypothesized that the antioxidant vitamin C may help reverse hyporesponsiveness to beta-adrenergic stimulation and improve myocardial efficiency in patients with heart failure (HF) after myocardial infarction (MI).. Nineteen patients with mild to moderate HF due to previous MI (mean left ventricular [LV] ejection fraction 39%) were instrumented with conductance and coronary sinus thermodilution catheters. Left ventricular contractility, expressed as E(es), the slope of end-systolic pressure-volume relationship, and mechanical efficiency, expressed as the ratio of LV stroke work (SW) to myocardial oxygen consumption (MVO2), were measured in response to the intravenous infusion of dobutamine (4 microg/kg per min) before (Dob) and during (Dob + Vit C) the infusion of vitamin C (2.0-g bolus injection and subsequent 50-mg/min infusion through the jugular vein) (vitamin C group, n = 10). The infusion of vitamin C augmented the E(es) response to dobutamine by 20% +/- 8% (Dob 2.1 +/- 0.3, Dob + Vit C 2.5 +/- 0.4 mm Hg/mL, P < .01) and the SW/MVO2 response by 21% +/- 5% (Dob 36% +/- 3%, Dob + Vit C 43% +/- 4%, P < .01). In the control group (n = 9), E(es) and SW/MVO2 were measured in response to dobutamine before (Dob) and during (Dob + vehicle) the infusion of saline. No difference in E(es) or SW/MVO2 was observed between Dob and Dob + vehicle (E(es): Dob 2.1 +/- 0.2, Dob + vehicle 2.1 +/- 0.2 mm Hg/mL per square meter, P = nonsignificant) (SW/MVO2: Dob 35% +/- 4%, Dob + vehicle 33% +/- 4%, P = nonsignificant).. The administration of the antioxidant vitamin C enhances the contractile response to dobutamine and improves myocardial efficiency in patients with HF.

Topics: Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Cardiac Catheterization; Cardiac Output; Cardiotonic Agents; Dobutamine; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Reactive Oxygen Species; Thermodilution; Ventricular Function, Left

Oxidative stress plays a role in the progression of chronic heart failure (CHF), but whether and how ischaemic heart disease (IHD) or non-IHD aetiology may account for differential redox alterations is currently unclear. We assessed the relation between thiol redox state and lipid peroxidation, as a marker of oxidative stress, in patients with CHF of ischaemic or non-ischaemic origin.. Blood reduced glutathione, plasma total and reduced cysteine, cysteinylglycine, homocysteine, glutathione, plasma alpha-tocopherol, ascorbic acid, and free malondialdehyde were assessed in 43 CHF heart transplant candidates (24 IHD and 19 non-IHD) and 30 controls matched for age, gender and number of atherosclerotic risk factors.. Reduced cysteine was increased in CHF patients compared with controls. The highest levels were found in IHD versus non-IHD patients versus controls. Malondialdehyde levels were significantly higher in IHD patients than in controls, whereas antioxidant vitamins did not differ among the three groups.. Specific abnormalities in the thiol pattern are associated with heart failure aetiology in CHF patients. Our findings point to the possible role of reduced cysteine in the progression of chronic IHD to heart failure status, as an additional pro-oxidant stimulus for worsening oxidative stress.

Topics: Aged; alpha-Tocopherol; Ascorbic Acid; Biomarkers; Case-Control Studies; Chronic Disease; Cysteine; Dipeptides; Disease Progression; Female; Glutathione; Heart Failure; Homocysteine; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Myocardial Ischemia; Oxidation-Reduction; Oxidative Stress; Research Design; Sulfhydryl Compounds

Oxidative stress plays an important role in mediating ventricular remodeling and dysfunction in heart failure (HF), but its mechanism of action has not been fully elucidated. In this study we determined whether a combination of antioxidant vitamins reduced myocyte apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular (SR) Ca2+ ATPase downregulation in HF after myocardial infarction (MI) and whether these effects were associated with amelioration of left ventricular (LV) remodeling and dysfunction. Vitamins (vitamin C 300 mg and vitamin E 300 mg) were administered to rabbits 1 week after MI or sham operation for 11 weeks. The results showed that MI rabbits exhibited cardiac dilation and LV dysfunction measured by fractional shortening and the maximal rate of pressure rise (dP/dt), an index of contractility. These changes were associated with elevation of oxidative stress, decreases of mitochondrial Bcl-2 and cytochrome c proteins, increases of cytosolic Bax and cytochrome c proteins, caspase 9 and caspase 3 activities and myocyte apoptosis, and downregulation of beta-adrenergic receptor sensitivity and SR Ca2+ ATPase. Combined treatment with vitamins C and E diminished oxidative stress, increased mitochondrial Bcl-2 protein, decreased cytosolic Bax, prevented cytochrome c release from mitochondria to cytosol, reduced caspase 9 and caspase 3 activities and myocyte apoptosis, blocked beta-adrenergic receptor desensitization and SR Ca2+ ATPase downregulation, and attenuated LV dilation and dysfunction in HF after MI. The results suggest that antioxidant therapy may be beneficial in HF.

Topics: Animals; Apoptosis; Ascorbic Acid; Blotting, Western; Calcium-Transporting ATPases; Down-Regulation; Echocardiography; Heart Failure; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mitochondria; Muscle Cells; Myocardial Infarction; Oxidative Stress; Rabbits; Receptors, Adrenergic, beta; Sarcoplasmic Reticulum; Ventricular Remodeling; Vitamin E; Vitamins

The 22 supersetnd Hohenheim Consensus Workshop took place in at the University of Stuttgart-Hohenheim. The subject of this conference was vitamin C and its role in the treatment of endothelial dysfunction. Scientists, who had published and reviewed scientific and regulatory papers on that topic were invited, among them basic researchers, toxicologists, clinicians and nutritionists. The participants were presented with eleven questions, which were discussed and answered at the workshop, with the aim of summarising the current state of knowledge. The explicatory text accompanying the short answers was produced and agreed on after the conference and was backed up by corresponding references. The therapeutic relevance of administration of the physiological antioxidant vitamin C in high parenteral doses in Endothelial Dependent Pathophysiological Conditions (EDPC) was discussed. Endothelial dysfunction is defined as including disturbed endothelial dependant relaxation of resistance vessels, breakdown of the microvascular endothelial barrier and/or loss of anti-adhesive function. It occurs in severe burn injury, intoxications, acute hyperglycemia, sepsis, trauma, and ischemic-reperfusion tissue injury and is induced by oxidative stress. Reduced plasma ascorbate levels are a hallmark of oxidative stress and occur in severe burns, sepsis, severe trauma, intoxication, chemotherapy/radiotherapy and organ transplantation. Vitamin C directly enhances the activity of nitric oxide synthase, the acyl CoA oxidase system and inhibits the actions of proinflammatory lipids. There is experimental evidence that parenteral high-dose vitamin C restores endothelial function in sepsis. In vitro, supraphysiological concentrations (> 1mM) of ascorbate restore nitric oxide bioavailability and endothelial function. Only parenterally, can enough vitamin C be administered to combat oxidative stress. There is no evidence that parenteral vitamin C exerts prooxidant effects in humans. Theoretical concerns in relation to competitive interactions between vitamin C and glucose cellular uptake are probably only relevant for oxidised vitamin C (dehydroascorbate).

Topics: Acute Disease; Acyl-CoA Oxidase; Ascorbic Acid; Burns; Endothelium, Vascular; Glucose; Heart Failure; Humans; Hyperglycemia; Infusions, Parenteral; Myocardial Ischemia; Nitric Oxide Synthase Type III; Oxidative Stress; Poisoning; Reperfusion Injury; Sepsis

It has been suggested that oxidative stress contributes to impaired left ventricular (LV) contractility in the setting of heart failure (HF). To test this hypothesis, we studied the effect of an antioxidant on contractility at rest and in response to dobutamine in 10 HF patients. We hypothesized that vitamin C would augment contractility in HF and that this effect would be of a greater magnitude in HF patients compared with patients with normal LV (NLV) function. Data from 10 patients with NLV function who participated in this study are included in this report and have been published elsewhere. A micromanometer-tipped catheter was introduced into the LV. In the experimental protocol, an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to the intravenous infusion of dobutamine before and during the intracoronary infusion of vitamin C (96 mg/min). Vitamin C had no effect on basal LV +dP/dt in either HF or NLV groups. The infusion of vitamin C augmented the LV +dP/dt response to dobutamine by 22 +/- 4% in the NLV function group. In contrast, vitamin C had no effect on the inotropic response to dobutamine in the HF group. In the control protocol, without vitamin C, no differences were observed between responses to two sequential dobutamine infusions in either group (HF, n = 11; NLV, n = 9). Therefore, a positive effect of vitamin C on contractility was limited to patients with NLV function. The absence of this effect in HF patients may suggest that normal redox responsiveness is lost in this disease state.

Topics: Ascorbic Acid; Cardiotonic Agents; Dobutamine; Female; Heart; Heart Failure; History, Early Modern 1451-1600; Humans; Male; Middle Aged; Myocardial Contraction; Oxidation-Reduction; Reference Values; Ventricular Dysfunction, Left

Topics: Antioxidants; Ascorbic Acid; Baroreflex; Heart Failure; Humans; Nervous System

A growing body of evidence supports the pathophysiologic role of oxidative stress and the protective role of naturally occurring antioxidants in congestive heart failure (CHF). Circulating levels of a sensitive and specific marker of lipid peroxidation and levels and activities of a broad spectrum of essential antioxidant micronutrients, vitamins, and enzymes, however, have been never simultaneously evaluated in well-characterized CHF patients.. Plasma levels of 8,12-isoprostane F(2alpha)-VI; vitamins A, C, and E; uric acid; and five carotenoids as well as activities of plasma superoxide dismutase and glutathione peroxidase were measured in 30 patients with class II and III New York Heart Association (NYHA) CHF and in 30 controls. Ejection fraction was measured in all patients. Significantly higher 8,12-isoprostane F(2alpha)-VI levels and lower antioxidant levels and activities were found in CHF patients in comparison to controls. Levels of 8,12-isoprostane F(2alpha)-VI were higher in class III than in class II NYHA CHF patients (P=.0012), and inversely correlated with ejection fraction; vitamins A, C, and E; uric acid; carotenoid levels; and superoxide dismutase activity.. There is an association between increased lipid peroxidation and both antioxidant status and disease severity in CHF in humans. These findings support the rationale for intervention trials aiming at exploring beneficial effects of antioxidant micronutrients in this disease.

Topics: Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Biomarkers; Carotenoids; Dinoprost; F2-Isoprostanes; Female; Glutathione Peroxidase; Heart Failure; Humans; Male; Severity of Illness Index; Statistics as Topic; Stroke Volume; Superoxide Dismutase; Uric Acid; Vitamin A; Vitamin E

Antioxidant vitamins reduce cardiac oxidative stress and cardiomyocyte apoptosis produced by exogenous norepinephrine (NE) and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure (CHF). This study was carried out to determine whether the mitogen-activated protein kinase (MAPK) signal transduction pathways are involved in oxidative stress-induced myocyte apoptosis. Rabbits with rapid pacing-induced CHF and sham operation were randomized to receive either a combination of antioxidant vitamins (beta-carotene, ascorbic acid, and alpha-tocopherol), alpha-tocopherol alone, or placebo for 8 wk. Compared with sham-operated animals, CHF animals exhibited increased oxidative stress as evidenced by decreased myocardial reduced-to-oxidized glutathione (GSH/GSSG) ratio (27 +/- 7 vs. 143 +/- 24, P < 0.05), myocyte apoptosis (77 +/- 18 vs. 17 +/- 4 apoptotic nuclei/10,000 cardiomyocytes, P < 0.05), increased total and phosphorylated c-Jun NH2-terminal protein kinase (p-JNK; 1.95 +/- 0.14 vs. 1.04 +/- 0.04 arbitrary units, P < 0.05) and phosphorylated p38 kinase (p-p38), and decreased phosphorylated extracellular signal-regulated kinase (p-ERK). Administration of antioxidant vitamins and alpha-tocopherol attenuated oxidative stress, myocyte apoptosis, and cardiac dysfunction, with reversal of the changes of total JNK, p-JNK, and p-ERK in CHF. Furthermore, because NE infusion produced changes of JNK, p-p38, and p-ERK similar to those in CHF, we conclude that NE may play an important role in the production of oxidative stress, MAPK activation, and myocyte apoptosis in CHF.

Topics: alpha-Tocopherol; Animals; Antibodies, Monoclonal; Antioxidants; Apoptosis; Ascorbic Acid; beta Carotene; Blotting, Western; Cardiac Pacing, Artificial; Chromans; DNA, Single-Stranded; Glutathione; Heart Failure; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinases; Myocardium; Myocytes, Cardiac; Norepinephrine; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rabbits; Superoxide Dismutase; Sympathomimetics

Chronic heart failure (CHF) reduces baroreflex sensitivity. Low baroreflex sensitivity, a risk factor for sudden death, could arise partly from CHF-dependent endothelial dysfunction. Vitamin C at high doses has a protective role against CHF-related endothelial damage. This study was conducted to investigate the effect of vitamin C on baroreflex sensitivity in CHF. A study group of 33 subjects with CHF secondary to postischemic dilated cardiomyopathy with an ejection fraction

Topics: Ascorbic Acid; Autonomic Nervous System; Baroreflex; Blood Pressure; Brachial Artery; Chronic Disease; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged

Building on the work of the late John Myers, MD, the author has used an intravenous vitamin-and-mineral formula for the treatment of a wide range of clinical conditions. The modified "Myers' cocktail," which consists of magnesium, calcium, B vitamins, and vitamin C, has been found to be effective against acute asthma attacks, migraines, fatigue (including chronic fatigue syndrome), fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other disorders. This paper presents a rationale for the therapeutic use of intravenous nutrients, reviews the relevant published clinical research, describes the author's clinical experiences, and discusses potential side effects and precautions.

Topics: Administration, Oral; Adult; Aged; Ascorbic Acid; Asthma; Body Temperature; Calcium Gluconate; Child, Preschool; Depression; Drug Combinations; Fatigue; Female; Fever; Fibromyalgia; Heart Failure; Humans; Hydroxocobalamin; Infusions, Intravenous; Magnesium Chloride; Male; Middle Aged; Migraine Disorders; Pantothenic Acid; Pyridoxine; Respiratory Tract Infections; Vitamin B Complex

High arterial blood oxygen tension increases vascular resistance, possibly related to an interaction between reactive oxygen species and endothelium-derived vasoactive factors. Vitamin C is a potent antioxidant capable of reversing endothelial dysfunction due to increased oxidant stress. We tested the hypotheses that hyperoxic vasoconstriction would be prevented by vitamin C, and that acetylcholine-mediated vasodilation would be blunted by hyperoxia and restored by vitamin C. Venous occlusion strain gauge plethysmography was used to measure forearm blood flow (FBF) in 11 healthy subjects and 15 congestive heart failure (CHF) patients, a population characterized by endothelial dysfunction and oxidative stress. The effect of hyperoxia on FBF and derived forearm vascular resistance (FVR) at rest and in response to intra-arterial acetylcholine was recorded. In both healthy subjects and CHF patients, hyperoxia-mediated increases in basal FVR were prevented by the coinfusion of vitamin C. In healthy subjects, hyperoxia impaired the acetylcholine-mediated increase in FBF, an effect also prevented by vitamin C. In contrast, hyperoxia had no effect on verapamil-mediated increases in FBF. In CHF patients, hyperoxia did not affect FBF responses to acetylcholine or verapamil. The addition of vitamin C during hyperoxia augmented FBF responses to acetylcholine. These results suggest that hyperoxic vasoconstriction is mediated by oxidative stress. Moreover, hyperoxia impairs acetylcholine-mediated vasodilation in the setting of intact endothelial function. These effects of hyperoxia are prevented by vitamin C, providing evidence that hyperoxia-derived free radicals impair the activity of endothelium-derived vasoactive factors.

Topics: Acetylcholine; Adult; Antioxidants; Ascorbic Acid; Blood Flow Velocity; Blood Pressure; Endothelium, Vascular; Female; Forearm; Heart Failure; Heart Rate; Humans; Hyperoxia; Male; Middle Aged; Oxidative Stress; Vascular Resistance; Vasoconstriction; Vasodilation; Verapamil

Cardiac hypertrophy is a significant risk factor for the development of congestive heart failure (CHF). Mitochondrial defects are reported in CHF, but no consistent mitochondrial alterations have yet been identified in hypertrophy. In this study selective metabolic inhibitors were used to determine thresholds for respiratory inhibition and to reveal novel mitochondrial defects in hypertrophy. Cardiac hypertrophy was produced in rats by aortic banding. Mitochondria were isolated from left ventricular tissue and the effects of inhibiting respiratory complexes I and IV on mitochondrial oxygen consumption were measured. At 8 weeks post-surgery, 65+/-2% complex IV inhibition was required to inhibit respiration half maximally in control mitochondria. In contrast, only 52+/-6% complex IV inhibition was required to inhibit respiration half maximally in mitochondria from hypertrophied hearts (P=0.046). This effect persisted at 22 weeks post-surgery and was accompanied by a significant upregulation of inducible nitric oxide synthase (iNOS, 3.0+/-0.7-fold, P=0.006). We conclude that respiration is more sensitive to complex IV inhibition in hypertrophy. Nitric oxide is a well documented inhibitor of complex IV, and thus the combination of increased NO(.)from iNOS and an increased sensitivity to inhibition of one of its targets could result in a bioenergetic defect in hypertrophy that may be a harbinger of CHF.

Topics: Animals; Aorta; Ascorbic Acid; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cardiomyopathy, Hypertrophic; Constriction; Cytochromes; Dose-Response Relationship, Drug; Electron Transport Complex I; Electron Transport Complex IV; Enzyme Induction; Fatty Alcohols; Heart Failure; Male; Mitochondria, Heart; NADH, NADPH Oxidoreductases; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroso Compounds; Oxidative Phosphorylation; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Uncoupling Agents

To assess whether systemic oxidative stress can predict the risk of first myocardial infarction, ischemic stroke, and congestive heart failure.. A longitudinal study started in 1992 and completed in 1997.. Community-based, outpatient.. 102 apparently healthy, community-dwelling subjects age 80 and older from the Vibrata valley, Teramo, Italy.. Plasma vitamin E, beta-carotene, vitamin C, fluorescent products of lipid peroxidation (FPLPs), and serum lipids were determined at enrollment.. Thirty-two cardiovascular events were recorded in 47.4 months of follow-up. The subjects with vitamin E levels in the highest quartile had a risk of cardiovascular events one-sixth those with vitamin E levels in the lowest quartile (relative risk (RR) = 0.16; 95% confidence interval (CI) = 0.04-0.55). The subjects with FPLPs in the highest quartile had a risk seven times greater than those with FPLPs in the lowest quartile (RR = 7.61; 95% CI = 2.23-25.96). No association was observed for vitamin C, beta-carotene, or total cholesterol. Multivariate adjustment for known risk factors did not significantly change the results.. Our results suggest that in apparently healthy, community-dwelling very old subjects, base-line plasma concentration of vitamin E and FPLPs predicts the risk of future cardiovascular events. We confirm previous data showing that total cholesterol is not a predictor of cardiovascular disease in people age 80 and older.

Topics: Age Distribution; Age Factors; Aged; Aged, 80 and over; Ascorbic Acid; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Heart Failure; Humans; Incidence; Italy; Lipid Peroxides; Longitudinal Studies; Male; Multivariate Analysis; Myocardial Infarction; Oxidative Stress; Predictive Value of Tests; Risk Factors; Stroke; Triglycerides; Vitamin E

We administered antioxidant vitamins to rabbits with pacing-induced cardiomyopathy to assess whether antioxidant therapy retards the progression of congestive heart failure (CHF).. Although oxidative stress is increased in CHF, whether progression of heart failure could be prevented or reduced by antioxidants is not known.. Rabbits with chronic cardiac pacing and sham operation were randomized to receive a combination of beta-carotene, ascorbic acid and alpha-tocopherol, alpha-tocopherol alone or placebo over eight weeks. Echocardiography was used to measure cardiac function weekly. Resting hemodynamics and in vivo myocardial beta-adrenergic responsiveness were studied at week 8. Animals were then sacrificed for measuring myocardial beta-receptor density, norepinephrine (NE) uptake-1 site density, sympathetic neuronal marker profiles, tissue-reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and oxidative damage of mitochondrial DNA (mtDNA).. Rapid cardiac pacing increased myocardial oxidative stress as evidenced by reduced myocardial GSH/GSSG ratio and increased oxidized mtDNA and produced cardiac dysfunction, beta-adrenergic subsensitivity, beta-receptor downregulation, diminished sympathetic neurotransmitter profiles and reduced NE uptake-1 carrier density. A combination of antioxidant vitamins reduced the myocardial oxidative stress, attenuated cardiac dysfunction and prevented myocardial beta-receptor downregulation and sympathetic nerve terminal dysfunction. Administration of alpha-tocopherol alone produced similar effects, but the effects were less marked than those produced by the three vitamins together. Vitamins produced no effects in sham-operated animals.. Antioxidant vitamins reduced tissue oxidative stress in CHF and attenuated the associated cardiac dysfunction, beta-receptor downregulation and sympathetic nerve terminal abnormalities. The findings suggest that antioxidant therapy may be efficacious in human CHF.

Topics: alpha-Tocopherol; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; beta Carotene; DNA, Mitochondrial; Down-Regulation; Echocardiography; Glutathione; Heart Failure; Hemodynamics; Myocardium; Neurotransmitter Agents; Oxidative Stress; Rabbits; Receptors, Adrenergic, beta; Sympathetic Nervous System

Chronic heart failure (CHF) seems to be associated with increased oxidative stress. However, the hypothesis that antioxidant nutrients may contribute to the clinical severity of the disease has never been investigated.. To examine whether antioxidant nutrients influence the exercise capacity and left ventricular function in patients with CHF.. Dietary intake and blood levels of major antioxidant nutrients were evaluated in 21 consecutive CHF patients and in healthy age- and sex-matched controls. Two indexes of the severity of CHF, peak exercise oxygen consumption (peak VO2) and left ventricular ejection fraction (LVEF), were measured and their relations with antioxidants were analysed.. Whereas plasma alpha-tocopherol and retinol were in the normal range, vitamin C (P=0.005) and beta-carotene (P=0.01) were lower in CHF. However, there was no significant association between vitamins and either peak VO2 or LVEF. Dietary intake (P<0.05) and blood levels of selenium (P<0.0005) were lower in CHF. Peak VO2 (but not LVEF) was strongly correlated with blood selenium: r=0.76 by univariate analysis (polynomial regression) and r=0.87 (P<0.0005) after adjustment for age, sex and LVEF.. Antioxidant defences are altered in patients with CHF. Selenium may play a role in the clinical severity of the disease, rather than in the degree of left ventricular dysfunction. Further studies are warranted to confirm the data in a large sample size and to investigate the mechanisms by which selenium and other antioxidant nutrients are involved in CHF.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; beta Carotene; Cardiomyopathies; Chronic Disease; Feeding Behavior; Female; Heart Failure; Humans; Male; Middle Aged; Oxidative Stress; Selenium; Ventricular Function, Left

Chronic excessive norepinephrine (NE) causes cardiac sympathetic nerve terminal abnormalities, myocardial beta-adrenergic receptor downregulation, and beta-adrenergic subsensitivity. The present study was carried out to determine whether these changes could be prevented by antioxidants.. Ferrets were administered either NE (1.33 mg/d) or vehicle by use of subcutaneous pellets for 4 weeks. Animals were simultaneously assigned to receive either antioxidant vitamins (beta-carotene, ascorbic acid, and alpha-tocopherol) or placebo pellets. NE increased plasma NE 4- to 5-fold but had no effect on heart rate, heart weight, arterial pressure, or left ventricular systolic function. However, myocardial NE uptake activity and NE uptake-1 site density were reduced, as well as cardiac neuronal NE, tyrosine hydroxylase, and neuropeptide Y. In addition, there was a decrease in myocardial beta-adrenergic receptor density with a selective decrease of the beta(1)-receptor subtype, reduction of the high-affinity site for isoproterenol, decreased basal adenylyl cyclase activity, and the adenylyl cyclase responses to isoproterenol, Gpp(NH)p, and forskolin. All of these changes were prevented by antioxidant vitamins. The effects of NE on myocardial beta-adrenergic receptor density, NE uptake-1 carrier site density, and neuronal NE were also prevented by superoxide dismutase or Trolox C.. The toxic effects of NE on the sympathetic nerve terminals are mediated via the formation of NE-derived oxygen free radicals. Preservation of the neuronal NE reuptake mechanism is functionally important, because the antioxidants also prevented myocardial beta-adrenergic receptor downregulation and postreceptor abnormalities. Thus, antioxidant therapy may be beneficial in heart failure, in which cardiac NE release is increased.

Topics: Adenylyl Cyclases; Adrenergic alpha-Agonists; Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Chromans; Ferrets; Free Radical Scavengers; Heart; Heart Failure; Heart Rate; Male; Myocardium; Norepinephrine; Polyethylene Glycols; Receptors, Adrenergic, beta; Recombinant Proteins; Superoxide Dismutase; Sympathetic Nervous System; Vitamin A; Vitamin E

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O(2)) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O(2) inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the alpha-adrenergic antagonist phentolamine during inhalation of either room air or 100% O(2), with and without the simultaneous infusion of ascorbic acid. Neither O(2) inhalation (3.9+/-0.4 compared with 3.8+/-0.3 ml.min(-1).100 ml(-1)) nor ascorbic acid infusion (5.2+/-0.4 compared with 5.5+/-0.4 ml.min(-1).100 ml(-1)) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O(2) inhalation or ascorbic acid infusion (room air, 140+/-55%; O(2), 118+/-46%; ascorbic acid, 147+/-39%; ascorbic acid+O(2), 109+/-31%). O(2) inhalation did, however, reduce the dilation induced by phentolamine (room air, 131+/-24%; O(2), 80+/-14%; P<0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O(2) inhalation suggests that degradation of NO by O(2)-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O(2) inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.

Topics: Acetylcholine; Arm; Ascorbic Acid; Biological Availability; Female; Heart Failure; Humans; Male; Middle Aged; Nitric Oxide; Oxygen Inhalation Therapy; Phentolamine; Plethysmography; Regional Blood Flow; Vascular Resistance; Vasodilator Agents

Impaired endothelium-dependent vasodilation has been reported to play an important role in the pathogenesis of cardiovascular diseases such as coronary artery disease (CAD) and congestive heart failure (CHF). However, the precise mechanism of endothelial dysfunction has not been elucidated in these conditions. To evaluate the role of oxidative stress in endothelial dysfunction, the effect of antioxidant ascorbic acid on brachial flow-mediated, endothelium-dependent vasodilation during reactive hyperemia and nitroglycerin-induced endothelium-independent vasodilation was examined with high resolution ultrasound in 12 patients with CHF caused by idiopathic dilated cardiomyopathy without established coronary atherosclerosis and in 10 patients with CAD. Flow-mediated vasodilation in CHF (4.4+/-0.5%) and CAD (4.0 - 0.8%) was significantly (p <0.05) attenuated compared with that in 10 control subjects (9.6+/-0.9%). However, nitroglycerin-induced vasodilation was similar in 3 groups (13.7+/-1.3% in control, 13.9+/-1.1% in CHF, 12.7+/-1.4% in CAD). Ascorbic acid could significantly improve flow-mediated vasodilation only in patients with CAD (9.1+/-0.9%) but not with CHF (5.6+/-0.6%), and had no influence on nitroglycerin-induced vasodilation (13.6+/-1.1% in CHF, 14.0+/-1.3% in CAD). These results suggest that, in brachial circulation, augmented oxidative stress mainly leads to endothelial dysfunction in CAD but not in CHF caused by idiopathic dilated cardiomyopathy.

Topics: Adult; Aged; Angina Pectoris; Ascorbic Acid; Blood Flow Velocity; Brachial Artery; Cardiomyopathy, Dilated; Coronary Disease; Endothelium, Vascular; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Nitroglycerin; Reproducibility of Results; Ultrasonography, Doppler; Vasodilation; Vasodilator Agents

Amyloidosis results from protein infiltration of the extracellular space of organs and tissues. Several amyloidosis proteins have been identified. Protein AL, (deriving from immunoglobulin light chain), protein AA and prealbumin are the most involved in this disease. When AL amyloidosis involves the heart, the illness is often terminal. Most clinical symptoms are heart failure and arrhythmia or block conduction. This case was characterised by the unusual combination of hypertension and amyloidosis. The diagnosis suggested by the echocardiographic but was confirmed by the damaged organ's biopsy. The present case concerns a young woman, who has hypertension and a pulmonary oedema. The echocardiographic scan showed a septal hypertrophy with a shining and granite-like aspect which is compatible with heart amyloidosis. Systolic and diastolic disorder with mitral and aortic regurgitation were also revealed. The kidney and rectum biopsies confirmed amyloidosis AL of the Kappa dysglobulinemia type, without extraosseous plasmocytoma. The heart and kidney failure symptoms disappeared after treatment with diuretics and ACE inhibitors.

Topics: Adult; Amyloidosis; Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid; Biopsy; Cardiomegaly; Colchicine; Diuretics; Echocardiography; Female; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Immunoglobulin kappa-Chains; Nephritis; Paraproteinemias; Pulmonary Edema; Radiography; Rectum

Topics: Animals; Ascorbic Acid; Dogs; Female; Heart Failure; Hemodynamics; Male; Rabbits

Topics: Ascorbic Acid; Heart Failure; Humans; Male; Middle Aged

Topics: Animals; Aprotinin; Ascorbic Acid; Drug Therapy, Combination; Glutamates; Glutamic Acid; Heart Failure; Ibuprofen; Myocardial Infarction; Myocardium; Nandrolone; Nandrolone Decanoate; Nifedipine; Potassium Magnesium Aspartate; Propranolol; Rabbits; Sodium Oxybate; Vitamin E

We describe rapidly fatal cardiomyopathy in a young man. He had for twelve months ingested large amounts of ascorbic acid and was admitted with severe heart failure having been symptomatic for two months. He died after eight days. Idiopathic haemochromatosis was diagnosed at autopsy. The clinical and laboratory features are discussed and the possible implications of ascorbic acid ingestion are explored.

Topics: Adult; Ascorbic Acid; Cardiomyopathies; Heart Failure; Hemochromatosis; Humans; Male; Myocardium

The application of noninvasive techniques to the evaluation of cardiac function in iron overload has identified a high incidence of abnormalities in asymptomatic patients prior to the onset of overt cardiac deterioration. Of the tests we have used, radionuclide cineangiography appears to be the most sensitive because it can be conveniently applied during the physiological stress of exercise. Other tests of cardiac function that include stress are also likely to be more sensitive than resting measurements of cardiac function. Systematic application of these techniques to the study of patients on iron chelation therapy should results in an early determination of the efficacy of such treatment.

Topics: Adolescent; Adult; Ascorbic Acid; Child; Child, Preschool; Deferoxamine; Heart; Heart Diseases; Heart Failure; Heart Function Tests; Humans; Iron; Thalassemia; Transfusion Reaction

Topics: Arm; Ascorbic Acid; Blood Circulation Time; Cardiac Catheterization; Femoral Artery; Heart Failure; Humans; Mitral Valve Stenosis; Pulmonary Artery

Topics: Acetylcholine; Adrenal Glands; Adrenal Medulla; Animals; Aortic Valve Insufficiency; Ascorbic Acid; Cardiomegaly; Catecholamines; Corticosterone; Heart; Heart Failure; Hypertension; Myocardium; Norepinephrine; Organ Size; Rabbits

Topics: Adult; Ascites; Ascorbic Acid; Benzothiadiazines; Child; Edema; Heart Failure; Humans

Topics: Acetylcholine; Adrenal Glands; Animals; Aorta; Ascorbic Acid; Corticosterone; Diphtheria Toxin; Electrocardiography; Heart; Heart Failure; Norepinephrine; Rabbits

Topics: Ascorbic Acid; Bendroflumethiazide; Diuretics; Edema, Cardiac; Electrolytes; Feeding and Eating Disorders; Geriatrics; Heart Failure; Humans; Hypertension; Nausea; Potassium; Toxicology; Vitamin B Complex; Vomiting

Topics: Ascorbic Acid; Diagnosis, Differential; Dogs; Electrocardiography; Heart Defects, Congenital; Heart Diseases; Heart Failure; Humans; Indicator Dilution Techniques; Mitral Valve Insufficiency; Mitral Valve Stenosis; Oximetry; Research

Topics: Arteriosclerosis; Ascorbic Acid; Blood Chemical Analysis; Cardiovascular Diseases; Coronary Disease; Geriatrics; Heart Failure; Humans; Hypertension

Topics: Ascorbic Acid; Carbohydrate Metabolism; Heart Failure; Humans

Topics: Ascorbic Acid; Child; Heart Failure; Humans; Infant; Kidney Diseases; Medical Records; Vitamins

Topics: Ascorbic Acid; Glycogen; Heart; Heart Failure; Myocardium; Sulfhydryl Compounds

Topics: Ascorbic Acid; Heart Failure; Humans; Lactic Acid; Vitamins

Topics: Ascorbic Acid; Blood; Body Fluids; Fasting; Heart Failure; Humans; Urine; Vitamins

Topics: Ascorbic Acid; Heart; Heart Failure; Organometallic Compounds; Purines

Topics: Ascorbic Acid; Diuretics; Heart; Heart Failure; Organometallic Compounds; Purines