4-hydroxy-2-nonenal and Heart-Failure

Mitochondrial dysfunction characterized by impaired bioenergetics, oxidative stress and aldehydic load is a hallmark of heart failure. Recently, different research groups have provided evidence that selective activation of mitochondrial detoxifying systems that counteract excessive accumulation of ROS, RNS and reactive aldehydes is sufficient to stop cardiac degeneration upon chronic stress, such as heart failure. Therefore, pharmacological and non-pharmacological approaches targeting mitochondria detoxification may play a critical role in the prevention or treatment of heart failure. In this review we discuss the most recent findings on the central role of mitochondrial dysfunction, oxidative stress and aldehydic load in heart failure, highlighting the most recent preclinical and clinical studies using mitochondria-targeted molecules and exercise training as effective tools against heart failure.

Topics: Aldehydes; Animals; Antioxidants; Biomimetic Materials; Cardiotonic Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Energy Metabolism; Exercise; Heart Failure; Humans; Malondialdehyde; Mitochondria, Heart; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Ubiquinone

A previous report by our team showed that Waon therapy, using a far infrared-ray dry sauna at 60°C, improves cardiac and vascular function in patients with chronic heart failure (CHF). The purpose of the present study was to clarify the effect of Waon therapy on oxidative stress in CHF patients and investigate its mechanism by animal experiments.. Forty patients with CHF were divided into control (n=20) and Waon therapy (n=20) groups. All patients received standard optimal medications for CHF. Waon therapy group was treated with Waon therapy daily for 4 weeks. After 4 weeks of Waon therapy, concentrations of hydroperoxide and brain natriuretic peptide (BNP) decreased significantly (hydroperoxide, 422±116 to 327±88U.CARR, P<0.001; BNP, 402±221 to 225±137pg/ml, P<0.001), and the nitric oxide metabolites increased (71.2±35.4 to 92.0±40.5mmol/L, P<0.05). In contrast, none of these variables changed over the 4-week interval in the control group. Furthermore, animal experiments were performed using TO-2 cardiomyopathic hamsters. On immunohistochemistry, cardiac expression of 4-hydroxy-2-nonenal, a marker of oxidative stress, was decreased in the 4-week Waon therapy compared to untreated hamsters. On Western blotting, cardiac expressions of heat shock protein (HSP) 27, manganese superoxide dismutase and HSP32, which reduce oxidative stress, were significantly upregulated in the 4-week Waon therapy compared to untreated hamsters.. Waon therapy decreases oxidative stress in patients and hamsters with heart failure.

Topics: Aged; Aldehydes; Animals; Biomarkers; Cardiomyopathy, Dilated; Cardiovascular Agents; Combined Modality Therapy; Cricetinae; Disease Models, Animal; Female; Gene Expression Regulation; Heart Failure; Heat-Shock Proteins; Hot Temperature; Humans; Hydrogen Peroxide; Infrared Rays; Male; Mesocricetus; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Oxidative Stress; Superoxide Dismutase

Topics: Heart Failure; Humans; MicroRNAs; Mitochondria; Protein Processing, Post-Translational

Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.. Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.. 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.. 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Heart Failure; Humans; MicroRNAs; Protein Processing, Post-Translational; Rats; Ribonuclease III

Deficiency of energy supply is a major complication contributing to the syndrome of heart failure (HF). Because the concurrent activity profile of mitochondrial bioenergetic enzymes has not been studied collectively in human HF, our aim was to examine the mitochondrial enzyme defects in left ventricular myocardium obtained from explanted end-stage failing hearts. Compared with nonfailing donor hearts, activity rates of complexes I and IV and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase, and aconitase were lower in HF, as determined spectrophotometrically. However, activity rates of complexes II and III and citrate synthase did not differ significantly between the two groups. Protein expression, determined by Western blotting, did not differ between the groups, implying posttranslational perturbation. In the face of diminished total glutathione and coenzyme Q10 levels, oxidative modification was explored as an underlying cause of enzyme dysfunction. Of the three oxidative modifications measured, protein carbonylation was increased significantly by 31% in HF (P < 0.01; n = 18), whereas levels of 4-hydroxynonenal and protein nitration, although elevated, did not differ. Isolation of complexes I and IV and F1FoATP synthase by immunocapture revealed that proteins containing iron-sulphur or heme redox centers were targets of oxidative modification. Energy deficiency in end-stage failing human left ventricle involves impaired activity of key electron transport chain and Krebs cycle enzymes without altered expression of protein levels. Augmented oxidative modification of crucial enzyme subunit structures implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, thus contributing further to reduced bioenergetics in human HF.

Topics: Aconitate Hydratase; Aldehydes; Blotting, Western; Citrate (si)-Synthase; Citric Acid Cycle; Electron Transport Chain Complex Proteins; Electron Transport Complex I; Electron Transport Complex IV; Female; Glutathione; Heart Failure; Heart Ventricles; Humans; Isocitrate Dehydrogenase; Ketoglutarate Dehydrogenase Complex; Malate Dehydrogenase; Male; Middle Aged; Mitochondria, Heart; Mitochondrial Proton-Translocating ATPases; Myocardium; Oxidative Phosphorylation; Protein Carbonylation; Protein Processing, Post-Translational; Reactive Oxygen Species; Ubiquinone

Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA).. Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R (2)=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only.. Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.

Topics: Aged; Aldehydes; Case-Control Studies; Cholesterol, HDL; Fatty Acids, Unsaturated; Female; Heart Failure; Humans; Linoleic Acid; Lipid Peroxidation; Male; Middle Aged

Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined.. Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2-knockout or ALDH2 mutant-overexpressing mice but were significantly attenuated in ALDH2-overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4-hydroxy-2-nonenal (4-HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4-HNE on the relevant cytosolic protective pathways. Our data documented 4-HNE-stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4-HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4-HNE instigated by downregulation of mitochondrial ALDH2.. Downregulation of ALDH2 in the mitochondria induced an elevation of 4-HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Disease Models, Animal; Down-Regulation; Heart Failure; HSP70 Heat-Shock Proteins; Humans; Hypertrophy, Left Ventricular; JNK Mitogen-Activated Protein Kinases; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Mitochondrial Proteins; Mutation; Myocardial Infarction; Myocardium; Phosphorylation; Rats, Sprague-Dawley; RNA Interference; Signal Transduction; Time Factors; Transfection; Tumor Suppressor Protein p53; Ventricular Dysfunction, Left; Ventricular Function, Left

The current study was designed to test the hypothesis that inducible nitric oxide synthase (iNOS)-mediated lipid free radical overproduction exists in an insulin-resistant rat model and that reducing the accumulation of toxic metabolites is associated with improved insulin signaling and metabolic response. Lipid radical formation was detected by electron paramagnetic resonance spectroscopy with in vivo spin trapping in an obese rat model, with or without thiazolidinedione treatment. Lipid radical formation was accompanied by accumulation of toxic end products in the liver, such as 4-hydroxynonenal and nitrotyrosine, and was inhibited by the administration of the selective iNOS inhibitor 1400 W. The model showed impaired phosphorylation of the insulin signaling pathway. Ten-day rosiglitazone injection not only improved the response to an oral glucose tolerance test and corrected insulin signaling but also decreased iNOS levels. Similar to the results with specific iNOS inhibition, thiazolidinedione dramatically decreased lipid radical formation. We demonstrate a novel mechanism where a thiazolidinedione treatment can reduce oxidative stress in this model through reducing iNOS-derived lipid radical formation. Our results suggest that hepatic iNOS expression may underlie the accumulation of lipid end products and that reducing the accumulation of toxic lipid metabolites contributes to a better redox status in insulin-sensitive tissues.

Topics: Aldehydes; Animals; Body Composition; Free Radicals; Glucose Intolerance; Heart Failure; Hypertension; Insulin Resistance; Lipid Peroxidation; Liver; Male; Muscle, Skeletal; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thiazolidinediones; Tyrosine

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H₂O₂ release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H₂O₂ resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca²⁺-induced permeability transition and reduced H₂O₂ release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a non-pharmacological tool for heart failure therapy.

Topics: Aldehydes; Animals; Calcium; Cells, Cultured; Exercise Therapy; Heart Failure; Hydrogen Peroxide; Male; Mitochondria, Heart; Muscle Proteins; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Oligopeptides; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Processing, Post-Translational; Rats; Rats, Wistar; Running

Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1 alpha) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1 alpha can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1 alpha deficiency (PGC-1 alpha(-/-)) on oxidative stress and expression of a group of mitochondrial antioxidants in normal hearts and in hearts exposed to chronic systolic pressure overload produced by transverse aortic constriction (TAC). We found that PGC-1 alpha(-/-) caused moderate but significant decreases of myocardial mitochondrial antioxidant enzymes such as SOD2, and thioredoxin (Trx2), but had no effect on expression of myocardial oxidative stress markers and left ventricular (LV) function under basal conditions. However, in response to TAC for 6 weeks, PGC-1 alpha(-/-) mice showed greater increases of myocardial oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal, more severe LV hypertrophy and dilatation, pulmonary congestion, and a greater reduction of LV fractional shortening and dP/dt(max) than did wild-type hearts. SOD mimetic MnTMPyP treatment (6 mg/kg/day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1 alpha(-/-) mice. These data indicate that PGC-1 alpha plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction.

Topics: Aldehydes; Animals; Antioxidants; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Myocardial Contraction; Myocardium; Nitroso Compounds; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species; Superoxide Dismutase; Systole; Thioredoxins; Trans-Activators; Transcription Factors; Tyrosine

Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability. This study tested the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in six dogs by ventricular pacing at 240 beats/min for 4 wk. Studies were performed at rest and during treadmill exercise under control conditions and after treatment with the NADPH oxidase inhibitor and antioxidant apocynin (4 mg/kg iv). Apocynin caused no significant changes in heart rate, aortic pressure, left ventricular (LV) systolic pressure, LV end-diastolic pressure, or maximum rate of LV pressure increase at rest or during exercise in normal or CHF dogs. Apocynin caused no change in coronary blood flow (CBF) in normal dogs but increased CBF at rest and during exercise in animals with CHF (P < 0.05). Intracoronary ACh caused dose-dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to ACh in normal dogs but augmented the response to ACh in CHF dogs (P < 0.05). The oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal were significantly greater in failing than in normal myocardium. Furthermore, coelenterazine chemiluminescence for O(2)(-) was more than twice normal in failing myocardium, and this difference was abolished by apocynin. Western blot analysis of myocardial lysates demonstrated that the p47(phox) and p22(phox) subunits of NADPH were significantly increased in the failing hearts, while real-time PCR demonstrated that Nox2 mRNA was significantly increased. The data indicate that increased ROS generation in the failing heart is associated with coronary endothelial dysfunction and suggest that NADPH oxidase may contribute to this abnormality.

Topics: Acetophenones; Acetylcholine; Aldehydes; Animals; Antioxidants; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Female; Heart Failure; Hemodynamics; Male; NADPH Oxidases; Oxidative Stress; RNA, Messenger; Superoxides; Tyrosine; Up-Regulation; Vasodilation; Vasodilator Agents

Oxidative stress is an important susceptibility factor for dilated cardiomyopathy. We have investigated the effects of bisoprolol, a beta1-selective adrenoceptor blocker, on oxidative stress and the development of cardiac dysfunction in a model of dilated cardiomyopathy. Male TO-2 and control hamsters at 8 weeks of age were treated with bisoprolol (5 mg/kg per day) or vehicle for 4 weeks. Treatment with bisoprolol prevented the progression of cardiac dysfunction in TO-2 hamsters. This drug did not affect the increase in NADPH oxidase activity but prevented the reduction in activity and expression of mitochondrial manganese-dependent superoxide dismutase as well as the increases in the concentrations of interleukin-1beta and tumor necrosis factor-alpha in the left ventricle of TO-2 hamsters. Attenuation of the development of cardiac dysfunction by bisoprolol may thus result in part from normalization of the associated increases in the levels of oxidative stress and pro-inflammatory cytokines in the left ventricle.

Topics: Aldehydes; Animals; Antioxidants; Bisoprolol; Blood Pressure; Body Weight; Cardiomyopathy, Dilated; Cricetinae; Disease Models, Animal; Echocardiography; Fibrosis; Glutathione; Heart Failure; Heart Rate; Interleukin-1; Isoenzymes; Male; NADPH Oxidases; Organ Size; Oxidative Stress; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Tyrosine; Ventricular Function, Left

Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism is not known. We examined whether oxidative stress was elevated in myocardia of HCM patients and whether the levels were correlated with left ventricular dilatation and systolic dysfunction.. Endomyocardial biopsy samples obtained from the right ventricular side of the septum of 31 patients with HCM, and 10 control subjects were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with HCM. Expression was distinct in the cytosol of cardiomyocytes. The expression levels in patients with HCM were significantly increased compared with those in control subjects (P = .0005). The expression levels in patients with HCM were correlated with left ventricular end-diastolic diameter (r = 0.483, P = .0053) and end-systolic diameter (r = 0.500, P = .0037) determined by echocardiography. The expression levels were inversely correlated with left ventricular ejection fraction determined by left ventriculography (r = -0.640, P = .0001).. Oxidative stress was elevated in myocardia of HCM patients and the levels were correlated with left ventricular dilatation and systolic dysfunction. Oxidative stress is involved in the pathogenesis of heart failure in patients with HCM.

Topics: Aldehydes; Biopsy; Cardiomyopathy, Hypertrophic; Case-Control Studies; Echocardiography; Female; Heart Failure; Humans; Immunohistochemistry; Lipid Peroxidation; Male; Middle Aged; Myocardium; Oxidative Stress; Stroke Volume; Systole; Ventricular Dysfunction, Left

In this study, we examined whether an angiotensin II type 1 (AT1)-receptor blocker improves diastolic heart failure (DHF) in Dahl salt-sensitive (DS) rats. DHF was prepared by feeding DS rats on 8% NaCl diet from 7 weeks of age. DHF was estimated with echocardiography by measuring E velocity / A velocity (E/A) of left ventricular inflow. DS rats with established DHF were orally given candesartan (1 mg/kg per day) or vehicle. After 13 days of treatment, candesartan significantly improved DHF, as shown by the reduction of E/A from 4.49 +/- 1.04 to 1.98 +/- 0.54 (P<0.05) and prolonged survival rate more than the vehicle. Cardiac fibrosis, apoptosis, and gene expression were estimated by Sirius Red-staining, TUNEL-staining, and Northern blot analysis, respectively. The improvement of DHF by candesartan was accompanied by the decrease in cardiac hypertrophy, fibrosis, and apoptosis, and the reduction of gene expression of brain natriuretic peptide, collagen I, and monocyte chemoattractant protein-1. Moreover, candesartan decreased cardiac inflammatory cells and reactive oxygen species, estimated by counting ED-1-positive cells and the measurement of 4-hydroxy-2-nonenal staining, respectively. These results indicate that candesartan can improve diastolic dysfunction and may slow the progression of cardiac remodelling in DS rats with established DHF.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Benzimidazoles; Biphenyl Compounds; Chemokine CCL2; Collagen Type I; Echocardiography, Doppler; Fibrosis; Gene Expression; Heart Failure; Immunohistochemistry; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; RNA, Messenger; Sodium Chloride, Dietary; Survival Rate; Tetrazoles

Lipid peroxidation generates several unsaturated aldehydes, such as 4-OH-nonenal (HNE), which may interact with and modify the function of other molecules that are of biological importance. Although congestive heart failure (CHF) is a state of generalized oxidative stress, the resultant spectrum of saturated and unsaturated aldehydes has not been systematically characterized in this condition.. We studied 8 CHF patients and 8 age-matched patients with normal left ventricular (LV) function. The concentrations of 22 aldehydes produced by lipid peroxidation, including saturated (n-alkanals) and unsaturated (t-2-alkenals, t-2,t-4-alkadienals, 4-OH-alkenals) aldehydes, were measured in arterial plasma by gas chromatography mass spectrometry (GC/MS). LV contractility (+dP/dt) and relaxation (Tau) were directly measured with a micromanometer-tipped catheter.. Compared with patients who have normal LV function, CHF patients had higher levels of total aldehydes (9,311 +/- 835 v 6,594 +/- 344 nmol/L, P < .01), as well as multiple unsaturated aldehydes (t-2-alkenals and 4-OH-alkenals, including HNE). In the CHF group, a strong relationship was observed between total aldehyde concentration and both +dP/dt (correlation coefficient = -0.76, P < .05) and Tau (correlation coefficient = 0.78, P < .05).. Unsaturated aldehyde levels were consistently elevated in the plasma of CHF patients compared with patients who have normal LV function. In CHF patients, elevated aldehyde levels were associated with impairment of LV contractility.

Topics: Aldehydes; Biomarkers; Cardiac Catheterization; Female; Gas Chromatography-Mass Spectrometry; Heart Failure; Humans; Lipid Peroxidation; Male; Middle Aged; Myocardial Contraction; Oxidative Stress; Prognosis; Ventricular Function, Left

For the first time it was demonstrated that 4-hydroxynonenal (HNE) is formed by the myocardium. 1 to 2 pmol HNE/min/mg protein were released from isolated perfused hearts of 18-month-old WKY rats during a normoxic period of perfusion. During the first minutes of reperfusion following 30 min of ischaemia, the mean value of HNE release increased in comparison to pre-ischaemic HNE release (pre-ischaemic control). However, the alterations were significant only in the second minute of reperfusion. HNE liberation significantly intensified during the early reperfusion period of hearts of 18-month-old spontaneously hypertensive rats (SHR, with cardiac hypertrophy and congestive heart failure) in comparison with the pre-ischaemic control period. Furthermore, HNE liberation from those hearts was higher than from hearts of normotensive control animals (WKY rats). Maximum quantities were observed 2 min after ischaemia, with 6 to 10 pmol HNE/min/mg protein. The results suggest that the formation of chemotactic products of radical-induced lipid peroxidation, such as HNE, is markedly increased in reperfused hypertrophic and failing myocardium, and emphasize the role of HNE as a possible chemotactic agent during postischaemic reoxygenation.

Topics: Aldehydes; Animals; Cardiomegaly; Chemotaxis, Leukocyte; Heart; Heart Failure; Inflammation; Lipid Peroxidation; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species