Stress In Heart Failure Research Articles

Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

ST2 in Heart Failure: Where Does This New Marker Fit in?

A member of the interleukin-1 receptor family, soluble ST2 (sST2), is a powerful marker of myocyte strain and vascular stress in heart failure and acute coronary syndrome, as well as numerous other cardio-pulmonary disease states. It is clinically useful in both the emergency department and hospital setting for predicting disease prognosis and mortality. Together with patient-specific characteristics, sST2 also has an increasing role to play as a tool to guide therapeutic interventions. We will discuss where this important new biomarker fits in now and its promise for the future.

Cardiac Oxidative Stress and Inflammatory Cytokines Response after Myocardial Infarction

Oxidative stress in heart failure or during ischemia/reperfusion occurs as a result of the excessive generation or accumulation of free radicals or their oxidation products. Free radicals formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. In the early phase of acute heart ischemia cytokines have the feature to be functional pleiotropy and redundancy, moreover, several cytokines exert similar and overlapping actions on the same cell type and one cytokine shows a wide range of biological effects on various cell types. Activation of cytokine cascades in the infarcted myocardium was established in numerous studies. In experimental models of myocardial infarction, induction and release of the pro-inflammatory cytokines like TNF-α (Tumor Necrosis Factor α), IL-1β (Interleukin- 1β) and IL-6 (Interleukin-6) and chemokines are steadily described. The current review examines the role of oxidative stress and pro-inflammatory cytokines response following acute myocardial infarction and explores the inflammatory mechanisms of cardiac injury.

Mitochondrion as a Target for Heart Failure Therapy- Role of Protein Lysine Acetylation.

Heart failure is a leading cause of death worldwide. Despite medical advances, the dismal prognosis of heart failure has not been improved. The heart is a high energy-demanding organ. Impairments of cardiac energy metabolism and mitochondrial function are intricately linked to cardiac dysfunction. Mitochondrial dysfunction contributes to impaired myocardial energetics and increased oxidative stress in heart failure, and the opening of mitochondrial permeability transition pore triggers cell death and myocardial remodeling. Therefore, there has been growing interest in targeting mitochondria and metabolism for heart failure therapy. Recent developments suggest that mitochondrial protein lysine acetylation modulates the sensitivity of the heart to stress and hence the propensity to heart failure. This article reviews the role of mitochondrial dysfunction in heart failure, with a special emphasis on the regulation of the nicotinamide adenine dinucleotide (NAD(+)/NADH) ratio and sirtuin-dependent lysine acetylation by mitochondrial function. Strategies for targeting NAD(+)-sensitive mechanisms in order to intervene in protein lysine acetylation and, thereby, improve stress tolerance, are described, and their usefulness in heart failure therapy is discussed.

Heart failure: mitochondrial dysfunction and oxidative stress in CHF.

The results of the Q-SYMBIO trial showing a reduction in mortality in patients with heart failure treated with coenzyme Q10 have substantial limitations. Nevertheless, they highlight the need to identify effective new therapies targeted at mitochondrial dysfunction and oxidative stress in heart failure.

The arterial chemoreflex and cardiac stress in heart failure: nothing to be sheepish about.

The arterial chemoreflex and cardiac stress in heart failure: nothing to be sheepish about.

Fear‐induced bradycardia is abnormal in rats with heart failure (1132.3)

We examined autonomic responses to fear in conscious rats with heart failure (HF) after myocardial infarction and central neural mechanisms for the responses. Rats exposed to 5‐min white noise sound (90 dB) displayed freezing behavior (an index of fear), renal sympathoexcitation, and bradycardia. The bradycardia was parasympathetically mediated since atropine injected intravenously prevented the response in normal rats (N5). In HF rats (N7, fractional shortening<35%), the fear‐induced bradycardia was significantly (P<0.05) larger than that in normal rats (N9). Of note, in HF rats, arrhythmia appeared in association with the reduction in heart rate seen during fear. Moreover, in normal rats (N7), microinjection into the lateral/ventrolateral periaqueductal gray (l/vlPAG) of muscimol, a GABAA receptor agonist, significantly suppressed the bradycardia response to fear. Lastly, in HF rats (N6), microinjection into the l/vlPAG of Tempol, a superoxide dismutase mimetic, significantly suppressed the bradycardia response to fear. Taken together, these results suggest that fear stimulates the l/vlPAG and parasympathetically causes bradycardia in rats, and that brain oxidative stress in HF leads to dysfunction of the l/vlPAG, thereby exaggerating parasympathetic effects on heart rate and elevating risks for cardiovascular events during fear. Supported by Shimane Pref Grant for regional medicine.

Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼ 80 to ∼ 170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼ 50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.

Significance of Neuropeptides for Coexistence of Disturbances in Central Cardiovascular Control in Heart Failure, Stress and Depression

There are solid grounds for the recognition of the involvement of multiple neuronal/neurotransmitter networks in the regulation of the cardiovascular system. Clinical and preclinical studies provide evidence that heart failure is associated with significant changes in the central control of some of these systems. In addition, it has been shown that some of the brain's neurochemical pathways, which are involved in the central control of blood pressure, play a role in the regulation of emotions and cognitive functions. Stress and depression are regarded as potential challenges for the cardiovascular system, causing inappropriate regulation of cardiovascular parameters and worsening the prognosis of heart failure. There is also evidence that heart failure increases sensitivity to stress and depression. Recently, knowledge of the neurochemical background of comorbidity of stress, depression and heart failure has increased markedly. Our studies and those of other authors provided evidence for significant role of the improper function of neuropeptides, and in particular of the angiotensinergic, vasopressinergic and oxytocinergic systems in the exaggerated responsiveness of the cardiovascular system to stress in heart failure and depression. Current evidence indicates that the inappropriate regulation of the release of these neuropeptides and/or expression of their receptors play a particularly important role in long-term changes of central cardiovascular control during post-infarct heart failure.

Angiotensin converting enzyme inhibition reduces cardiovascular responses to acute stress in myocardially infarcted and chronically stressed rats.

Previous studies showed that chronically stressed and myocardially infarcted rats respond with exaggerated cardiovascular responses to acute stress. The present experiments were designed to elucidate whether this effect can be abolished by treatment with the angiotensin converting enzyme (ACE) inhibitor captopril. Sprague Dawley rats were subjected either to sham surgery (Groups 1 and 2) or to myocardial infarction (Groups 3 and 4). The rats of Groups 2 and 4 were also exposed to mild chronic stressing. Four weeks after the operation, mean arterial blood pressure (MABP) and heart rate (HR) were measured under resting conditions and after application of acute stress. The cardiovascular responses to the acute stress were determined again 24 h after administration of captopril orally. Captopril significantly reduced resting MABP in each group. Before administration of captopril, the maximum increases in MABP evoked by the acute stressor in all (infarcted and sham-operated) chronically stressed rats and also in the infarcted nonchronically stressed rats were significantly greater than in the sham-operated rats not exposed to chronic stressing. These differences were abolished by captopril. The results suggest that ACE may improve tolerance of acute stress in heart failure and during chronic stressing.

Chronic inhibition of cGMP‐specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure

Inhibition of the cGMP-specific phosphodiesterase 5 (PDE5) exerts profound beneficial effects on failing hearts. However, the mechanisms underlying the therapeutic effects of PDE5 inhibition on heart failure are unclear. The purpose of this study was to investigate whether PDE5 inhibition decreases endoplasmic reticulum (ER) stress, a key event in heart failure. Heart failure was induced by isoprenaline s.c. injection in Sprague-Dawley rats and transverse aortic constriction (TAC) in mice. PDE5 was inhibited with sildenafil. Heart function was detected by invasive pressure-volume analysis and echocardiography. ER stress markers were analysed by Western blotting. Apoptosis was measured by flow cytometric analysis. PDE5 inhibition markedly attenuated isoprenaline-induced and TAC-induced cardiac hypertrophy and dysfunction, and reduced ER stress and apoptosis. Further, PDE5 inhibition with sildenafil largely prevented ER stress and reduced apoptosis in isoprenaline- or thapsigargin-treated cardiomyocytes. PKG inhibition markedly prevented the protective effects of sildenafil in vivo and in vitro. To further understand the mechanism of the effect of PDE5 inhibition on ER stress, we demonstrated that PDE5 inhibitor increased sarco-(endo)-plasmic reticulum Ca(2+) -ATPase activity via phosphorylation of phospholamban at Ser(16) . This may contribute to the attenuation of ER stress induced by PDE5 inhibition. These results suggest that PDE5 inhibition can attenuate ER stress and improve cardiac function in vivo and in vitro. Suppression of ER stress by inhibiting PDE5 may contribute to the therapeutic effects on heart failure.

Interplay of Mitochondrial Biogenesis and Oxidative Stress in Heart Failure

The dawn of mitochondrially powered cells began 1 to 2 billion years ago when an amitochondriate host subsumed α-proteobacterium, a hydrogen-producing symbiont.1 Equipped to oxidize nutrients, eukaryotic cells acquired a boost to cellular energy, enabling the emergence of multicellular mammals, sustained by a nearly inexhaustible muscular pump: the heart. Article see p 1957 In this issue of Circulation , Ahuja et al2 examine the interplay of mitochondria biogenesis and oxidative stress in human cardiomyopathy. They reveal that disparate changes in mitochondrial biogenesis and mitochondrial oxidative stress distinguish between ICM and DCM. Using a complement of ultrastructural, biochemical, and genetic analyses, Ahuja et al convincingly show that mitochondrial content is increased in dilated cardiomyopathic (DCM) hearts (n=8) but not ischemic cardiomyopathic (ICM) hearts (n=8). Regardless of the type of heart failure, oxidative phosphorylation (OXPHOS) was severely impaired, a finding universally reported by others. Given that mitochondrial content was increased ≈2-fold in DCM hearts, these data may imply better maintenance of total cellular OXPHOS in DCM hearts compared with ICM hearts. Because mitochondrial mass is influenced by proliferation (mitochondrial biogenesis) and clearance (mitophagy), the authors investigated the mechanistic basis for increased mitochondrial content in DCM hearts. Notably, PGC-1α (PPARGC1α ), a potent regulator of mitochondrial biogenesis,3 and several target genes of PGC-1α were induced at the level of mRNA and protein in DCM hearts but not in ICM hearts. These genetic data replicate a previously reported study.4 Even so, this topic is not immune to controversy or the Proteus phenomenon; findings by others oppugn the conclusions of Ahuja et al. Using a mixed cohort, 1 study showed that PGC-1α, which promotes mitochondrial biogenesis, was reduced in both ICM and DCM hearts.5 Induction of adenine nucleotide translocator ( SLC25A4 ), a gene with an induction that signifies mitochondrial biogenesis, was reported …

Algisyl-LVR™ with coronary artery bypass grafting reduces left ventricular wall stress and improves function in the failing human heart

Left ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients. Magnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264 ± 91 ml to 146 ± 86 ml and ESV decreased from 184 ± 85 ml to 86 ± 76 ml. Ejection fraction increased from 32 ± 8% to 47 ± 18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06 ± 0.21 cm (baseline) to 1.3 ± 0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV. These results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function.

Vascular function and the role of oxidative stress in heart failure, heart transplant, and beyond.

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.

Basic Science of Cardiac Resynchronization Therapy

Electromechanical dyssynchrony can markedly worsen heart failure (HF) morbidity and mortality, independent of traditional risk factors.1–4 Depending on the metric used, current estimates of the prevalence of dyssynchrony vary from 25–30% in patients with HF (based on QRS widening) up to 60%, based on tissue Doppler or MRI measures of dyssynchronous contraction of the left ventricle (LV).5,6 Cardiac resynchronization therapy (CRT) or biventricular pacing has emerged as a promising option to treat patients with HF and dyssynchronous contraction.7–9 The past few decades have seen the rise of pharmacotherapy, primarily through agents that antagonize the effect of excessive concentrations of circulating neurohormones, yet, HF-related morbidity and mortality remain high.3–6 Biventricular stimulation has been demonstrated to improve contractile performance in patients with mechanical dyssynchrony acutely and chronically while also prolonging long-term survival—something not yet achieved by drug therapy.10 Although the clinical and mechanical effectiveness of CRT are well described, 30% of patients do not benefit from CRT and clinical criteria to identify CRT nonresponders remain elusive8,11,12 Currently, the most widely used predictor of reverse remodeling is the presence of marked mechanical dyssynchrony before CRT, as indexed by the width of the QRS.13 Mechanical dyssynchrony seems important, yet imaging-based measures have not predicted response well14 and even improvement in dyssynchrony after initiation of CRT only weakly predicts chronic response.15 Limited understanding of the molecular mechanisms underlying reverse cardiac remodeling induced by CRT has hampered the selection of potential responders. In this review, we focus on the electrophysiological aspects and molecular networks underlying the benefits of CRT. We will review how CRT homogenizes regional differences in stress kinase signaling and electric remodeling and then review its global effect on myocyte function and its …

Signaling pathways involved in skeletal muscle response to oxidative stress in rats with heart failure

This study examined whether mitogen‐activated protein kinases (MAPK) and nuclear factor‐kappaB (NF‐κB) pathways participate in skeletal muscle response to oxidative stress in heart failure rats.MethodsMyocardial infarction (MI) was induced by left coronary occlusion. Four months later, rats were assigned to three groups: Sham (n=8), MI without treatment (n=8), and MI/NAC (MI treated with the antioxidant N‐acetylcysteine, 120 mg/kg/day, n=8). Rats with small MI were excluded. Six months after surgery, total and phosphorylated forms of MAPK (JNK and p38) and NF‐κB proteins were analyzed by Westen blot in soleus muscle.ResultsMI size did not differ between MI and MI/NAC groups (P&gt;0.05; Student's t test). Total JNK, p‐p38 and p‐NF‐κB did not differ among the groups. Table shows the other Western blot results.ConclusionSkeletal muscle response to oxidative stress is combined with JNK and NF‐κB protein expression changes in rats with heart failure. Support: FAPESP, CNPq, and Fundunesp.

Pharmacologic Strategies to Target Oxidative Stress in Heart Failure

Reactive oxygen species (ROS), which are involved in normal physiological functions at low concentrations, can have deleterious effects when produced in excess. Over time, ROS may result in a pathological state of imbalance known as oxidative stress. Oxidative stress has long been implicated in many diseases, and is consistently associated with poor outcomes in heart failure. Most therapies that are currently being used may provide some reduction in oxidative stress, but there is no consensus on the clinical outcomes of various antioxidants. Currently, there are no antioxidant therapies that are being used routinely to specifically target oxidative stress in patients with heart failure. This article reviews the current understanding of ROS generation, and the potential for novel pharmacologic strategies to target oxidative stress in heart failure.

Anti-oxidized low-density lipoprotein antibodies in chronic heart failure

Oxidative stress may play a significant role in the pathogenesis of heart failure (HF). Antibodies to oxidized low-density lipoprotein (oxLDL Abs) reflect an immune response to LDL over a prolonged period and may represent long-term oxidative stress in HF. The oxLDL plasma level is a useful predictor of mortality in HF patients, and measurement of the oxLDL Abs level may allow better management of those patients. Antibodies to oxLDL also significantly correlate with the New York Heart Association score. Hypercholesterolemia, smoking, hypertension, and obesity are risk factors for atherosclerotic coronary heart disease (CHD) leading to HF, but these factors account for only one-half of all cases, and understanding of the pathologic process underlying HF remains incomplete. Nutrients with antioxidant properties can reduce the susceptibility of LDL to oxidation. Antioxidant therapy may be an adjunct to lipid-lowering, angiotensin converting enzyme inhibition and metformin (in diabetes) therapy for the greatest impact on CHD and HF. Observational data suggest a protective effect of antioxidant supplementation on the incidence of HD. This review summarizes the data on oxLDL Abs as a predictor of morbidity and mortality in HF patients.

Examining the Interrelatedness of Patient and Spousal Stress in Heart Failure

Recent research has highlighted the positive influence that spouses can have on patient outcomes. It is not clear whether patients and spouses influence each other's well-being reciprocally or whether spousal well-being affects the success of patients' disease management. Our goals were 2-fold: (a) to propose a conceptual framework to examine the reciprocity between patient and spouses' well-being, especially as it relates to disease management, and (b) to begin to assess the validity of this model using pilot data. Twenty-three veterans with heart failure (HF) and their spouses were recruited into a pilot cross-sectional observational study. Participants completed psychosocial surveys to assess depressive symptoms, caregiver burden, relationship satisfaction, and disease management. Descriptive analyses and bivariate correlations between these measures were calculated. Using standard cutoffs, analyses suggested clinically significant depressive symptoms in patients (Center for Epidemiological Studies-Depression score >16; mean, 21.8 [SD, 13]) and a high level of caregiver burden among spouses (Zarit Burden Interview score >15; mean, 22.4 [SD, 15.4]). Both patients and spouses reported high relationship satisfaction levels (Dyadic Adjustment Scale score >100; mean, 112.6 [SD, 26.5] and 115.9 [SD, 14.4], respectively). On average, patients reported poor disease management (Self-care of Heart Failure Index subscale <70 across all subscales: confidence = 53.3 [SD, 28.2]; maintenance = 59.7 [SD, 17.3]; management = 54.0 [SD, 19.4]). Patient depressive symptoms were positively correlated with spouse depressive symptoms (r = 0.53) and caregiver burden (r = 0.64; all P's < .05). Spouses' depressive symptoms were additionally correlated with lower levels of perceived social support among patients (r = -0.47), poor patient relationship satisfaction (r = -0.51), and worse patient confidence in HF management (r = -0.48). Greater caregiver burden was associated with more patient disease complaints (r = 0.49), poorer patients' relationship satisfaction (r = -0.72), and poorer patients' perceived social support (r = -0.73). These results provide preliminary support to the proposed conceptual model. Further research is necessary to determine which spousal factors appear to be most relevant to disease management. Disease management interventions may benefit from engaging spouses in a way that enhances their role without adding to their burden.

Oxidative Stress in Heart Failure: What Are We Missing?

Over the past several decades, investigations in humans and animal models of heart failure (HF) have provided substantial evidence that oxidative stress is increased in HF and contributes to disease progression. The high metabolic activity of cardiac myocytes makes these cells active sources of reactive oxygen species. Work in cell and animal models clearly demonstrates that oxidative stress activates processes such as changes in gene expression and cell death that are now accepted components of myocardial remodeling and HF. Antioxidants prevent progressive remodeling and even improve cardiac function in animal models of HF. It is therefore disappointing that to date no antioxidant strategy has translated to a therapeutic in the HF clinic. Possible explanations, including inadequate appreciation of the critical disease-modifying sources of reactive oxygen species, the choice of the wrong antioxidant strategy, or incomplete understanding of individual variability in human antioxidant defenses in this brief review.