Stress In Chronic Heart Failure Research Articles

A Single Arm Clinical Study on the Effects of Continuous Erythropoietin Receptor Activator Treatment in Non-Dialysis Patients with Chronic Heart Failure and Renal Anemia

Erythropoiesis-stimulating agents improve the NYHA functional class and decrease the hospital readmission rates for heart failure; however, little is known about the influence of continuous erythropoietin receptor activator (CERA) on the heart. Therefore, a prospective study was conducted to investigate the effects of CERA on cardiac and renal function and oxidative stress in chronic heart failure with renal anemia. Sixty patients with chronic heart failure and renal anemia were enrolled and received CERA for 12 months. The primary endpoints were hemoglobin (Hb) and hematocrit, and the secondary endpoints were: (1) atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP); (2) NYHA class; (3) echocardiography; (4) blood urea nitrogen, creatinine, cystatin C, and urinary albumin; (5) high-sensitivity C-reactive protein; (6) oxidized low-density lipoprotein (Ox-LDL); and (7) renin, angiotensin-II, and aldosterone. There was a significant difference in the Hb levels measured before and after CERA administration. The BNP, ANP, NYHA, left ventricular mass index, renal function, and Ox-LDL decreased significantly after CERA administration. This study shows that CERA improves anemia and reduces renal impairment, as well as cardiac and oxidative stress. The result of this study is useful for a study in which switching from CERA to a new renal anemia drug, hypoxia-inducible factor prolyl-hydroxylase inhibitor, is investigated.

The Role of Psychological Stress on Heart Autophagy in Mice With Heart Failure

Psychological stress in chronic heart failure (CHF) is associated with systemic neurohormonal and immune system responses and increased mortality. Autophagy refers to the biological process of degradation and recycling of dysfunctional cellular components. We investigated the role of psychological stress on autophagy function in CHF mice. C57BL/6 mice underwent transverse aortic constriction, with or without combined acoustic and restraint stress, and cardiac function was assessed by echocardiography analysis. Serum corticosterone and angiotensin II (Ang II) were determined using enzyme-linked immunosorbent assay (ELISA). Autophagy and oxidative stress were measured with immunohistochemistry and quantitative polymerase chain reaction, and chloroquine and rapamycin were used to detect autophagy flux. In vivo, cardiomyocytes were cultured with or without Ang II or N-acetylcysteine, and autophagy and oxidative stress were also detected. A 1-week stress exposure significantly increased serum levels of corticosterone and Ang II (p = .000), increased levels of oxidative stress, induced overt heart failure, and increased mortality (p = .002). Furthermore, stress exposure unregulated messenger RNA expression of Bcl-2-interacting coiled-coil protein 1 (10.891 [3.029] versus 4.754 [1.713], p = .001), cysteine-rich domain containing beclin-1 interacting (6.403 [1.813] versus 3.653 [0.441], p = .006), and autophagy 7 (111.696 [4.049] versus 6.189 [1.931], p = .017), increased expression of autophagosomal, and decreased clearance of autophagosomes. In vitro, Ang II significantly increased autophagy flux in cultured cardiomyocytes, which could be partly inhibited by N-acetylcysteine. Psychological stress may contribute to the development of CHF by enhancing heart oxidative stress and impairing autophagy flux.

Muscle sympathetic nerve activity response to heat stress is attenuated in chronic heart failure patients.

Heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. The MSNA response to heat stress in chronic heart failure (CHF) is unknown. We hypothesized that the MSNA response to heat stress is attenuated in CHF. Passive whole body heating was applied with water-perfused suits in 13 patients (61 ± 2 yr) with stable class II-III CHF, 12 age-matched (62 ± 2 yr) healthy subjects, and 14 young (24 ± 1 yr) healthy subjects. Mild heating (i.e., increases in skin temperature ΔTsk ~2-4°C, internal temperature ΔTcore <0.3°C) significantly decreased MSNA in CHF patients; however, it did not significantly alter the MSNA in the age-matched and young healthy subjects. Heat stress (i.e., ΔTsk ~4°C and ΔTcore ~0.6°C) raised MSNA in the age-matched (32.9 ± 3.2 to 45.6 ± 4.2 bursts/min; P < 0.001) and young (14.3 ± 1.7 to 26.3 ± 2.4 bursts/min; P < 0.001) controls, but not in CHF (46.2 ± 5.3 to 50.5 ± 5.3 bursts/min; P = 0.06). The MSNA increase by the heat stress in CHF (Δ4.2 ± 2.0 bursts/min) was significantly less than those seen in the age-matched (Δ12.8 ± 1.7 bursts/min, P < 0.05) and young (Δ12.0 ± 2.7 bursts/min, P < 0.05) control groups. These data suggest that the MSNA response to heat stress is attenuated in CHF patients. We speculate that the attenuated MSNA response to heat stress may contribute to impaired cardiovascular adjustments in CHF in a hot environment.

Statins and oxidative stress in chronic heart failure

Statins are the most commonly prescribed drugs for the treatment of dyslipidemia. They are also recommended in primary and secondary prevention of cardiovascular disease. In addition to decreasing cholesterol synthesis, statins interfere with the synthesis of isoprenoid intermediates, which may explain many of their pleiotropic properties, including their antioxidant effects.Oxidative stress is defined as an imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems, with a prevailing pro-oxidant status that results in macromolecular damage and disruption of cellular redox signaling. Reactive oxygen species interfere with various processes that affect cardiac structure and function, contributing to the contractile dysfunction, myocardial hypertrophy and fibrosis observed in the pathophysiology of heart failure. By regulating several molecular pathways that control nicotinamide adenine dinucleotide phosphate oxidase and endothelial nitric oxide synthase activity, statins help restore redox homeostasis. These drugs also contribute to the control of inflammation and appear to have a protective role in various diseases. The results of observational studies and clinical trials with statins in heart failure have not been consensual.This review aims to analyze the role of oxidative stress in heart failure and the molecular mechanisms underlying statins’ antioxidant properties. It also examines current scientific evidence on the use of these drugs as a specific treatment for heart failure.

Abstract 9909: Selenium Supplementation Rescues Cardiac Function in Patients With Severe Heart Failure Who are Intractable to Renin-Angiotensin System Inhibitors and β-blockers

Introduction: Increases in oxidative stress may be involved in the progression of heart diseases. Selenium (Se) is an integral part of the enzyme glutathione peroxidase (GSHPx), one of the central players of the heart’s antioxidant system. This study evaluated Se supplementation in patients with severe heart failure who were intractable to renin-angiotensin system (RAS) inhibitors and β-blockers. Methods: In order to confirm the activation of myocardial oxidative stress and the local deficiency of GSHPx, we examined immunohistochemical staining of endomyocardial biopsy specimens obtained from 24 dilated cardiomyopathy (DCM) patients and analyzed serum Se concentrations and GSHPx activities. We enrolled patients who had shown no functional improvements after RAS inhibitors and β -blockers (n = 11). The patients were supplied with 25 μg of Se chloride twice per day while their other medications remained unchanged. Results: Compared with patients with normal ventricular function (n = 30), the serum Se concentrations and GSHPx activities from the patients with DCM (n = 24) were decreased by 55% (0.167 μg/ml vs 0.076 μg/ml, p &lt; 0.01), and by 33% (328 μmol/min/L vs 221 μmol/min/L, p &lt; 0.01), respectively. Myocardial biopsy from DCM patients, but not control patients, uniformly showed marked reduction of GSHPx stains (24/24 vs 0/3, respectively) that was accompanied by positive staining for both 4-hydroxy-2nonenal (20/24 vs 1/3) and 8-hydroxy-2`-deoxyguanosine (16/24 vs 0/3). Left ventricular (LV) ejection fraction increased from 26% ± 8% to 34% ± 8%, 37% ± 12%, and 38% ± 11% at the 3-month follow-up, 6-month follow-up, and 12-month follow-up, respectively, and then maintained thereafter. Conclusions: Our study suggests that myocardial oxidative stress in chronic heart failure may be augmented at least in part by concomitant GSHPx deficiency, and that the administration of Se could rescue the exhaustion of this selenoprotein, resulting in improved LV function.

OP-023 Oxidative Stress in Chronic Heart Failure and Elevated Programmed Cell Death

OP-023 Oxidative Stress in Chronic Heart Failure and Elevated Programmed Cell Death

Cardiovascular Responses to Heat Stress in Chronic Heart Failure

Clinical reports have suggested that patients with heart diseases may be particularly vulnerable to heat injury. This review examines the effects of heat stress on cardiovascular and autonomic functions in patients with chronic heart failure (CHF). Laboratory investigations have shown that cutaneous vasodilator responses to heating are impaired in patients, whereas activation of skin sympathetic nerve activation is not attenuated in CHF as compared to controls. Attenuated cutaneous vasodilation may increase the risk of a heat related illness when CHF subjects are exposed to hyperthermic conditions.

Abstract 528: Response of Muscle Sympathetic Nerve Activity to Heat Stress is Attenuated in Chronic Heart Failure

Cutaneous vascular conductance (CVC) rises during heat stress in normal humans. Recently, we showed that this response is attenuated in chronic heart failure (CHF), even though the skin sympathetic nerve activity response to heat stress was not attenuated. Of note, heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. This effect may allow flow to be distributed to other tissues. The MSNA response to heat stress in CHF has not been reported. We postulated that in CHF the MSNA response to heat stress is attenuated. Passive whole body heating was applied with water-perfused suits on 9 male (60 ± 3 yrs) patients with stable class II-III CHF and 9 age-matched male healthy subjects. Whole body heating induced similar increases in skin temperature (~4 °C), internal temperature (~0.6 °C), similar reduction in blood pressure, and similar increase in heart rate. The elevation in forearm CVC in CHF patients was significantly lower than that in healthy control subjects (102 ± 29 vs. 312 ± 54 units, P &lt; 0.001). While baseline MSNA in CHF was higher than in controls ( P &lt; 0.05); heat stress increased MSNA in the controls (33.2 ± 3.8 to 47.3 ± 4.4 bursts/min; 618 ± 74 to 934 ± 93 units/min, both P &lt; 0.001, N = 9), but not in CHF (43.4 ± 5.7 to 49.6 ± 7.0 bursts/min; 996 ± 104 to 1039 ± 108 units/min, both P &gt; 0.15, N = 6; two-factor ANOVA with repeated measure on one factor). Moreover, the MSNA change by heating in CHF was significantly lower than that in the controls (6.2 ± 2.6 to 14.1 ± 1.5 bursts/min; 43 ± 45 to 316 ± 34 units/min; both P &lt; 0.01, unpaired t-test). The attenuated MSNA response to heating was not due to a ceiling effect as that static fatiguing handgrip in CHF in a control trial evoked significant increases in MSNA. These data show that the MSNA response to heat stress is attenuated in CHF patients. We postulate that the attenuated MSNA response contributes to an impaired re-distribution of blood low to the skin during heat stress in CHF.

Beta-Blocker Therapy Causes Ventricular Reverse Remodeling Along with Inhibition of Collagen Degradation and Reduction of Ventricular Wall Stress in Chronic Heart Failure

Beta-Blocker Therapy Causes Ventricular Reverse Remodeling Along with Inhibition of Collagen Degradation and Reduction of Ventricular Wall Stress in Chronic Heart Failure

Markers of Oxidative Damage and Antioxidant Enzyme Activities as Predictors of Morbidity and Mortality in Patients With Chronic Heart Failure

BackgroundAlthough the majority of previous findings unequivocally confirmed the existence of systemic oxidative stress in chronic heart failure (CHF) patients, data on prognostic potential of biomarkers of oxidative lipid and protein damage are limited. We aimed to address the relation of oxidative stress markers to severity and prognosis in CHF secondary to ischemic cardiomyopathy. Methods and ResultsPlasma malondialdehyde (MDA), protein thiol groups (P-SH), reactive carbonyl derivatives (RCD), together with glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined in 120 CHF patients and 69 healthy controls. Increased lipid peroxidation (MDA) and oxidation of plasma proteins (RCD; P-SH) s well as downregulated GSH-Px activity were found in CHF patients compared with controls. Significant correlation was obtained only for RCD content and remodeling indices (LVEDV: r = 0.469, P = .008; LVESV: r = 0.452; P = .011). Cox regression analysis demonstrated only MDA (HR = 3.33; CI: 1.55–7.12; P = .002) as independent predictor of death, whereas SOD was associated with unstable angina pectoris (HR = 2.09; CI: 1.16–3.78; P = .011). ConclusionsIn the course of CHF progression, carbonyl stress is implicated in the LV remodeling. Malondialdehyde level might be a useful parameter for monitoring and planning management of CHF patients.

Conflicting effects of nitric oxide and oxidative stress in chronic heart failure: potential therapeutic strategies

Chronic heart failure (CHF) is characterized by decreased nitric oxide (NO) bioavailability. In addition, the beneficial NO turns to be deleterious when it reacts with superoxide anion, leading to peroxynitrite formation. Numerous experimental and clinical studies have reported increased production of reactive oxygen species (superoxide, hydrogen peroxide, hydroxyl radical) both in animals and patients with CHF. Moreover, there are indicative data suggesting mechanisms associated with endothelial dysfunction in states of CHF, mainly attributed to decreased NO bioavailability and enhanced inactivation of the latter. Thus, such molecules appear to be potential targets in patients with CHF. These patients are strong candidates to receive a variety of therapeutic agents, some of which have known antioxidant effects. Classic treatment with statins or angiotensin converting enzyme inhibitors has been found to be beneficial in restoring NO and improving myocardial function and structure. Other agents such as sildenafil and b-blockers along with novel agents such as NO synthase transcription enhancers have been proved to be also beneficial, but their use for such a purpose is still controversial. Approaches using more-effective antioxidants or targeting myocardial oxidant-producing enzymes and oxidative or nitrosative stress might be promising strategies in the future.

Nutritional intake and oxidative stress in chronic heart failure

Background and aimsPatients with chronic heart failure (CHF) are known to be at risk of malnutrition, and cardiac cachexia is an adverse prognostic indicator. The aim of this study was to determine the dietary adequacy of CHF patients compared with Dietary Reference Values, to compare the nutritional intake and status of CHF patients to a healthy comparison group, and finally to determine whether nutritional intake and status depended on New York Heart Association (NYHA) functional class. Methods and ResultsPatients with CHF (n = 39) and a comparison group of 27 healthy participants, who did not have CHF, were asked to complete a four-day food diary, and energy and nutrient intakes were calculated. F2α-isoprostanes were measured in urine as an indicator of oxidative stress and antioxidants were measured in serum or plasma. Overall 73% of the CHF patients were consuming less than recommended energy intakes, and more than 50% of these patients were also consuming less than recommended vitamin D, selenium and zinc intakes. Nutrient intake (energy, vitamin B6, D, E, iron, folate and riboflavin) was lower in CHF patients than in the comparison group, with vitamin B6 and folate intake and antioxidant status decreasing, and isoprostane status increasing as NYHA functional class increased. ConclusionThe majority of CHF patients do not meet dietary reference values for energy and a range of nutrients, and nutrient intake is lower in CHF patients than in healthy individuals. Dietary inadequacy tends to be increased in those with more severe disease.

Effect of Waon Therapy on Oxidative Stress in Chronic Heart Failure

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.

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

Endothelial function is impaired by oxidative stress in chronic heart failure (HF). Mechanisms that protect against increases in oxidative stress in HF are not clear. The goal of this study was to determine whether manganese superoxide dismutase (MnSOD) plays a key role in protecting against endothelial dysfunction in HF. Endothelial function and gene expression were examined in aorta from wild-type mice (MnSOD(+/+)) and mice deficient in MnSOD (MnSOD(+/-)) 12 wk after ligation of the left coronary artery (LCA). LCA ligation produced similar size myocardial infarctions in MnSOD(+/+) and MnSOD(+/-) mice and reduced ejection fraction to approximately 20% in both groups. Maximal relaxation in response to acetylcholine was 78 +/- 3% (mean +/- SE) and 66 +/- 8% in sham-operated MnSOD(+/+) and MnSOD(+/-) mice, respectively. Expression of antioxidant enzymes increased in MnSOD(+/+) mice with HF, and maximal relaxation to acetylcholine was slightly impaired (68 +/- 4%). Greater endothelial dysfunction was observed in MnSOD(+/-) mice with HF (46 +/- 5%, P < 0.05), which was significantly improved by polyethylene glycol-catalase but not Tempol. Incubation with the nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1 inhibitor valeryl salicylate, but not the COX-2 inhibitor NS-398, significantly improved relaxation to acetylcholine in HF mice (maximum relaxation = 74 +/- 5, 91 +/- 1, and 58 +/- 5%). These data suggest that MnSOD plays a key role in protecting against endothelial dysfunction in HF. A novel mechanism was identified whereby chronic increases in oxidative stress, produced by mitochondrial SOD deficiency, impair vascular function via a hydrogen peroxide-dependent, COX1-dependent, endothelium-derived contracting factor.

Skeletal Muscle Overexpression of SOD Normalizes the Exaggerated Exercise Pressor Reflex in Rats with Heart Failure

An sensitized exercise pressor reflex (EPR) in chronic heart failure (CHF), is believed to contribute to the exaggerated sympatho‐excitation observed during exercise in the CHF state. Accumulating evidence also shows that the exaggerated EPR in CHF may be due to an enhanced skeletal muscle mechanoreflex. However, the cause of the exaggerated EPR and the enhanced mechanoreflex in CHF are not well understood. Here, we hypothesized that muscle oxidative stress in CHF contributes to the exaggerated EPR and the enhanced mechanoreflex. We used the technique of adenoviral gene transfer to overexpress SOD proteins (AdSOD1 or AdSOD2, 1×1012 particles in saline/ml, 50 μl, Adempty as a control) in the triceps surae muscle of CHF rats (2‐4 weeks). The EPR was induced by static contraction in response to electrical stimulation of the ventral roots (L4/L5) in decerebrate rats. The mechanoreflex was induced by passive stretch in decerebrate rats. Table 1 shows the effect of overexpression of SOD proteins on the EPR and mechanoreflex in CHF rats. These data indicate that muscle oxidative stress contributes to the exaggerated EPR and the enhanced mechanoreflex in CHF. Effect of overexpression of SOD on the pressor response evoked by static contraction (EPR) or passive stretch in CHF rats. image Values are Mean±SE, n=6 in each group,*P&lt;0.05 vs Sham, ?P&lt;0.05 vs CHF+Empty.

MnSOD protects against COX1‐mediated endothelial dysfunction in chronic heart failure

Endothelial function is impaired by oxidative stress in chronic heart failure (CHF). Mechanisms that protect against increases in oxidative stress in CHF are not unclear. We examined endothelial function in aorta in wild‐type mice (MnSOD+/+) and mice deficient in manganese superoxide dismutase (MnSOD+/−) 12 weeks after ligation of the left cornary artery (LCA). LCA ligation produced similar size infarctions in MnSOD+/+ and MnSOD+/− mice. Maximal relaxation in response to acetylcholine was 78 ± 3% (mean ± SE) and 66 ± 8% in sham‐operated MnSOD+/+ and MnSOD+/−mice, respectively. Induction of CHF increased MnSOD expression ~1.7 fold in MnSOD+/+ mice, but not in MnSOD+/− mice. Maximal relaxation to acetylcholine was impaired in MnSOD+/+ mice (68 ± 4%), with greater impairments in endothelial function in MnSOD+/− mice with CHF (46 ± 5%). Incubation of vessel rings with Tempol did not improve vasorelaxation in response to acetylcholine. However, incubation with nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1‐specific inhibitor valeryl salicylate significantly improved relaxation to acetylcholine in CHF mice (maximum relaxation = 74 ± 5% and 91 ±1%, respectivley). Collectively, these data identify a novel mechanism whereby chronic increases in mitochondrial‐mediated oxidative stress impair vascular function via a COX1‐mediated endothelium‐derived contracting factor in CHF.

Exercise training improves the exercise pressor reflex dysfunction via ameliorating the skeletal muscle oxidative stress in chronic heart failure

In chronic heart failure (CHF), overactive skeletal muscle exercise pressor reflex (EPR) contributes to the exaggerated cardiovascular activity. It has been shown that exercise training (EX) improves the cardiovascular reflexes via ameliorating oxidative stress in CHF. In the present study, we tested the hypothesis that 6–8 weeks EX improved EPR in CHF rats via the mechanism of superoxide. EPR was elicited by electrical stimulation of L4/L5 ventral roots in the decerebrate rats. Superoxide fluorescence in the triceps surae muscle was enhanced in CHF rats compared with sham rats, which was reduced in EX+CHF rats. As shown in table, the EPR response in CHF rats was higher than in sham rats, and the intra‐arterial infusion of a superoxide dismutase (SOD) mimetic (tempol) normalized the EPR in CHF rats. EX improved the augmented EPR in CHF rats, which was abolished by the intra‐arterial infusion of a SOD inhibitor (DETC). The data suggest that EX improves the EPR dysfunction in CHF probably by ameliorating the muscle oxidative stress.

Genetic modification of vascular endothelial function as therapeutic strategy in heart failure

in patients with chronic heart failure, endothelial dysfunction contributes to increased systemic vascular resistance, decreased exercise tolerance, and reduced tissue perfusion. One of the better-characterized mechanisms responsible for endothelial dysfunction is the increased production of

Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure

We examined the hypothesis that oxidants generated nitroso derivatives, activated latent matrix metalloproteinase (MMP), and induced proteinase-activated receptor 1 (PAR-1), leading to disconnection between the endothelium and myocytes. Administration of cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4/CIMP) ameliorated the oxidative-proteolytic stress and endothelial-myocyte uncoupling in chronic heart failure (CHF) in mice. Aortic-vena cava fistula (AVF) was created in 30 male mice (C57BL/6J) and studied at 0-, 2-, and 8-wk AVF. To reverse cardiac remodeling, as measured by MMP activation, purified CIMP was administered by an osmotic minipump subcutaneously after 8-wk AVF, and groups of mice (n = 6 mice/group) were examined after 12 and 16 wk. Levels of PAR-1 in the left ventricle (LV) were increased at 2 and 8 wk (compared with 0 wk of no CIMP treatment) but were normal at 12 and 16 wk after CIMP treatment, as measured by Western blot analysis. Similar results were obtained for LV levels of nitrotyrosine, MMP-2 and -9 activities, and TIMP-1 and -3. However, the levels of TIMP-4, endothelial cell density, and responses of cardiac rings to acetylcholine and bradykinin were attenuated at 2 and 8 wk and normalized after CIMP administration in AVF mice. CIMP induced nitric oxide in microvascular endocardial endothelial cells. The results suggest that nitro generation activated MMP and PAR-1, leading to endothelial-myocyte uncoupling. CIMP treatment normalized PAR-1 expression and ameliorated endothelial-myocyte uncoupling by decreasing oxidant-mediated proteolytic stress in CHF.

Elevated circulating levels of thioredoxin and stress in chronic heart failure

Chronic heart failure (CHF) is a complex syndrome, in which reactive oxygen species and inflammatory cytokines are important stressors that contribute to the pathogenesis. We have studied physiological stress response parameters in CHF, in particular the redox-active regulator thioredoxin. A case-control study was conducted including a consecutive sample of CHF patients (n=27) of NYHA class II and III; comparison control subjects (n=29) were recruited from an association for retired people. Baseline levels of Trx, lipid peroxides (oxidative stress), TNF and IL-6 cytokines, platelet-activation marker P-selectin, cortisol (as peripheral effector of HPA axis), and the potent antioxidant selenoprotein Trx-reductase were assessed. Mean (+/-S.E.M.) plasma levels of Trx were significantly higher in patients with CHF (32+/-3 ng/ml), than in the healthy subjects (12+/-3 ng/ml, P<0.0001). Trx levels increased in proportion to severity of disease (NYHA class III>NYHA class II) and degree of stress. Trx elevation correlated well with increased oxidative stress (lipid peroxides, P<0.0001), circulatory P-selectin (P<0.0001), morning level of free salivary cortisol (P=0.0002), and serum creatinine (P=0.0417), but not with pro-inflammatory cytokines TNF and IL-6. Trx was strikingly elevated in heart failure cases compared with controls, signifying an adaptive stress response that is higher the more severe the disease.