Dose response biology of resveratrol in obesity

Obesity is a major health problem throughout the world, and it is increasing both in prevalence and severity. Pharmaceutical approaches developed for the treatment of obesity, despite short-term benefits, often are associated with rebound weight gain after the cessation of drug use and serious side effects deriving from the medication can occur. Resveratrol has been well recognized as an anti-obesity substance for its lipid-lowering function as well as calorie-restriction effect. This polyphenol induces hormetic dose responses in a wide range of biological models, affecting numerous endpoints of biomedical and therapeutic significance. From an hormetic standpoint, we will discuss the potential relevance of resveratrol in the management of obesity and related comorbid conditions, emphasizing its ability to control simultaneously various pathological mechanisms associated with obesity.     

Antithrombotic therapy in heart failure

Patients with congestive heart failure have a significant risk of stroke due to thromboembolism from the dilated left ventricle. Two relatively small trials suggest that oral anticoagulation with vitamin-K antagonists may reduce this risk when compared with placebo, aspirin or clopidogrel. However, more studies are eagerly awaited. So far, physicians seeing patients with heart failure should decide who needs antithrombotic prophylaxis on a case-by-case basis, especially since most heart failure patients have significant comorbidity precluding the use of oral anticoagulant.     

New aspects of impaired mitochondrial function in heart failure

This minireview focuses on the impairment of function in cardiac mitochondria in heart failure (HF). It is generally accepted that chronic energy starvation leads to cardiac mechanical dysfunction in HF. Mitochondria are the primary ATP generator for the heart. Current evidence suggests that the assembly of the electron transport chain (ETC) into respirasomes provides structural support for mitochondrial oxidative phosphorylation by facilitating electron channeling and perhaps by preventing electron leak and superoxide production. Defects have been purported to occur in the individual ETC complexes or components of the phosphorylation apparatus in HF, but these defects have not been linked to impaired mitochondrial function. Moreover, studies that reported decreased mitochondrial oxidative phosphorylation in HF did not identify the site of the defect. We propose a sequential mechanistic pathway in which the decrease in functional respirasomes in HF is the primary event causing decreased oxidative phosphorylation and increased reactive oxygen species production, leading to a progressive decrease in cardiac performance.     

Downregulation of Sirt1 as aging change in advanced heart failure

Background

In congestive heart failure the balance between cell death and cell survival in cardiomyocytes is compromised. Sirtuin 1 (Sirt1) activates cell survival machinery and has been shown to be protective against ischemia/reperfusion injury in murine heart. The role of Sirt1 in heart failure, especially in human hearts is not clear.

Results

The expression of Sirt1 and other (associated) downstream molecules in human cardiomyocytes from patients with advanced heart failure was examined. Sirt1 was down-regulated (54.92% ± 7.80% in advanced heart failure samples compared with healthy control cardiomyocytes). The modulation of molecules involved in cardiomyocyte survival and death in advanced heart failure were also examined. The expression of Mn-superoxide dismutase and thioredoxin1, as well as an antiapoptotic molecule, Bcl-xL, were all significantly reduced in advanced heart failure cardiomyoctes (0.71 ± 0.02-fold, 0.61 ± 0.05-fold, and 0.53 ± 0.08-fold vs. control, respectively); whereas the expression of proapoptotic molecule Bax was significantly increased (1.62 ± 0.18-fold vs. control). Increased TUNEL-positive number of cardiomyocytes and oxidative stress, confirmed by 8-hydorxydeoxyguanosine staining, were associated with advanced heart failure. The AMPK-Nampt-Sirt1 axis also showed inhibition in advanced heart failure in addition to severely impaired AMPK activation. Increased p53 (acetyl form) and decreased FoxO1 translocation in the nucleus may be the mechanism of down-regulation of antioxidants and up-regulation of proapoptotic molecules due to low expression of Sirt1.

Conclusion

In advanced heart failure, low Sirt1 expression, like aging change may be a significant contributing factor in the downregulation of antioxidants and upregulation of proapoptotic molecules through the p53, FoxO1, and oxidative stress pathways.     

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm). Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current- and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates. Accepted: 1 March 2000     

Quercetin and resveratrol potently reduce estrogen sulfotransferase activity in normal human mammary epithelial cells

Estrogen sulfotransferase (EST) is the sole sulfotransferase expressed in normal human breast epithelial cells and has an important function in determining free estrogen hormone levels in these cells. In the present study we examined the inhibitory effect of the dietary polyphenols quercetin and resveratrol on EST activity, i.e. 17β-estradiol (E2) sulfation. Both the compounds potently inhibited recombinant human EST in a competitive fashion with K_i values of about 1 μM. In fact, both polyphenols could serve as substrates for EST. In order to extend the studies to more physiologically relevant conditions, we examined whether inhibition of EST also occurred in the intact cultured human mammary epithelial (HME) cells. The mean baseline EST activity (E2 sulfate formation) in the HME cells was 4.4 pmol/h per mg protein. The IC₅₀ for resveratrol was very similar to that for recombinant EST, i.e. about 1 μM. Surprisingly, quercetin was 10 times more potent in the HME cells with an IC₅₀ of about 0.1 μM, a concentration that should be possible to achieve from the normal dietary content of this flavonoid.     

Preexisting heart failure is an underestimated risk factor in cardiac surgery

Background

Heart failure is characterised as a strong risk factor for systemic failure after cardiac surgery. However, the impact has never been substantiated.

Methods

Patients with heart failure (n = 48) - scheduled for elective ventricular reconstruction or external constraint device-were compared with a one-to-one matched control group of patients without heart failure undergoing cardiac surgery between 2006 and 2009.

Results

As expected, patients with heart failure more frequently experienced complications definitely related to pump failure (p = 0.01). However, complications not related to their pump failure were also more often observed, such as prolonged mechanical ventilation, sepsis and vasoplegia (p = 0.01). Overall, organ dysfunction-circulatory, renal, and pulmonary failure-was often observed in heart failure patients, contributing to a prolonged stay in the intensive care unit (p < 0.001) as well as in hospital (p = 0.01).

Conclusion

The adverse postoperative course in patients with heart failure is not only directly related to circulatory failure, but merely reflects a systemic dysregulation. Our findings suggest that heart failure impacts outcome and should therefore be included in prevailing risk classification systems. Offensive perioperative treatment strategies, focused on the main complications in patients with heart failure, will lead to improved results after cardiac surgery.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-012-0257-y) contains supplementary material, which is available to authorized users.     

伊伐布雷定治疗高龄老年射血分数中间值心衰患者的疗效观察

目的 评价伊伐布雷定治疗高龄老年射血分数中间值心衰(HFmrEF)患者的临床疗效.方法 选择我院治疗的120例高龄老年HFmrEF患者,按随机数字表法分为观察组和对照组各60例,对照组给予规范化抗心衰治疗,观察组在此基础上加用伊伐布雷定治疗.随访6个月后,比较两组治疗前后静息心率(RHR)、氨基末端脑钠肽前体(NT-p...     

心肌球源性细胞在心力衰竭中的应用

冠状动脉或其分支阻塞而引起心肌缺血可导致急性心肌梗死,梗死区域周围形成瘢痕组织后心脏收缩功能下降,心室发生病理性重塑,最终出现充血性心力衰竭。心肌球源性细胞（CDC）是来自心肌的干细胞,在体外可以分化为心肌细胞和血管内皮细胞。在体内可以触发自身心肌细胞增殖和通过旁分泌募集祖细胞。旁分泌介质不但拥有干细胞的作用,且没有细胞移植相关的并发症。临床实验证明了CDC可以促进心肌梗死后的心脏功能的恢复。长期疗效还有待大规模临床试验的验证。     

Low YKL-40 in chronic heart failure may predict beneficial effects of statins: analysis from the controlled rosuvastatin multinational trial in heart failure (CORONA)

Context and objective: To evaluate if YKL-40 can provide prognostic information in patients with ischemic heart failure (HF) and identify patients who may benefit from statin therapy.

Materials and methods: The association between serum YKL-40 and predefined outcome was evaluated in 1344 HF patients assigned to rosuvastatin or placebo.

Results: YKL-40 was not associated with outcome in adjusted analysis. In YKL-40 tertile 1, an effect on the primary outcome (HR 0.50, p?=?0.006) and CV death (HR 0.54, p?=?0.040) was seen by rosuvastatin in adjusted analysis.

Conclusions: A beneficial modification of outcome was observed with statin therapy in patients with low YKL-40 levels.     

The physiological role of cardiac cytoskeleton and its alterations in heart failure

Cardiac muscle cells are equipped with specialized biochemical machineries for the rapid generation of force and movement central to the work generated by the heart. During each heart beat cardiac muscle cells perceive and experience changes in length and load, which reflect one of the fundamental principles of physiology known as the Frank–Starling law of the heart. Cardiac muscle cells are unique mechanical stretch sensors that allow the heart to increase cardiac output, and adjust it to new physiological and pathological situations. In the present review we discuss the mechano-sensory role of the cytoskeletal proteins with respect to their tight interaction with the sarcolemma and extracellular matrix. The role of contractile thick and thin filament proteins, the elastic protein titin, and their anchorage at the Z-disc and M-band, with associated proteins are reviewed in physiologic and pathologic conditions leading to heart failure. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé     

Plasma levels and diagnostic value of catestatin in patients with heart failure

Catestatin (CST) is an endogenous neuropeptide with multiple cardiovascular activities. The study is to investigate circulating CST levels in heart failure (HF) patients and to evaluate the role of CST as a biomarker for HF. Plasma CST concentrations were measured by enzyme-linked immunosorbent assay in 228 HF patients and 172 controls. Plasma CST gradually increased in patients from NYHA class I to class IV. No significant differences in CST were found among NYHA I, NYHA II patients and controls. Plasma CST in NYHA III and IV patients was higher compared to other groups. Plasma CST levels in HF patients after treatment were similar to admission, but still higher than controls. In a subgroup analysis among the patients with NYHA class III or IV, patients with ischemic etiology had significantly higher CST. Plasma CST levels were similar between patients with preserved and reduced ejection fraction. Multivariable analysis showed that NYHA classes, the etiology of HF (ischemic or not) and estimated glomerular filtration rate independently predicted plasma LogCST levels (P < 0.05). The area under ROC for CST and BNP in moderate to severe HF diagnosis was 0.626 and 0.831, respectively, combining CST and BNP did not improve the accuracy.     

应用C-反应蛋白区别急性失代偿性心力衰竭与肺炎

目的研究通过测定入院时C-反应蛋白（CRP）水平和CRP速度来鉴别急性失代偿性心力衰竭（ADHF）与肺炎的功效。方法回顾性研究三级医院两年的ADHF与肺炎患者的病例资料。住院时已经用抗生素治疗的患者除外。CRP作为诊断标志物的有效性通过ROC来评估。结果 72例ADHF和50例肺炎患者被纳入研究。ADHF患者入院时平均CRP水平为（13.5±13.5）mg/L,而肺炎患者为（127±84）mg/L（P〈0.001）。CRP增加大于等于0.56 mg/（L·h）时诊断肺炎。入院时CRP水平和CRP升高作为区别肺炎与ADHF的标记物时的敏感度是0.96,特异性为0.972。结论本研究强调生物标志物的动态特性,证实了急性期反复测量CRP的有效性,它将为临床医生提供有价值的工具来建立正确的诊断及减少不必要的抗生素使用。     

Intracellular magnesium in elderly patients with heart failure: Effects of diabetes and renal dysfunction

Hypomagnesemia is frequent in diabetes mellitus (DM), while renal dysfunction (RD) may be associated with hypermagnesemia. Severe cardiac arrhythmias and other adverse clinical manifestations are frequent in heart failure (HF), in DM and in RD. Depletion of intracellular magnesium (icMg), which may coexist with normal serum Mg, might contribute to these deleterious effects. However, icMg content in normomagnesemic HF patients with RD or DM has not been studied. We assessed total icMg in peripheral blood mononuclear cells (PBMC) from 80 normomagnesemic furosemide-treated HF patients who were divided as follows: subgroups A (DM), B (RD), C (DM and RD), and D (free of DM or RD). PBMC from 18 healthy volunteers served as controls. IcMg content (μg/mg cell protein) in HF was lower compared to controls (1.68±0.2 vs. 2.4±0.39, p<0.001). In the entire HF group, a significant inverse correlation was evident between icMg and serum creatinine (r=−0.37) and daily furosemide dosages (r=−0.121). IcMg in the HF subgroups A, B, C, and D was 1.79±0.23, 1.57±0.23, 1.61±0.25, and 1.79±0.39, respectively (p=0.04 between A and B, p=0.08 between B and D, and non-significant in the remaining comparisons). Serum Mg, potassium, calcium, furosemide dosages and left ventricular ejection fraction were comparable in all subgroups. In conclusion, icMg depletion was demonstrable in PBMC, which may be responsible for some of the adverse clinical manifestations in HF patients. In particular, icMg depletion in RD might contribute to cardiac arrhythmias in this patient group. Mg supplementation to normomagnesemic HF patients might therefore prove beneficial.     

Oxidative stress and ischemia-modified albumin in chronic ischemic heart failure

Abstract

Objectives

Knowledge about the role of oxidative stress in human diseases, including cardiovascular system disorders, emphasizes the need for reliable markers of oxidative stress. Here, we evaluated the levels of the novel marker ischemia-modified albumin (IMA), albumin-adjusted IMA (adj-IMA), and the IMA/serum albumin ratio (IMAR) in patients with chronic ischemic heart failure (CIHF).

Methods

A total of 55 patients with CIHF and 40 age- and sex-matched healthy individuals were included in the study. Serum levels of IMA, total antioxidant status, and total oxidant status were analyzed, and the adj-IMA level, IMAR, and oxidative stress index were calculated.

Results

Serum IMA, IMAR, total oxidant status levels, and oxidative stress index were significantly higher in patients with CIHF than in the controls (all P < 0.0001), whereas albumin and total antioxidant status levels were significantly lower in the CIHF patients (P < 0.0001 and P = 0.0004, respectively). However, there was no significant difference in serum adj-IMA levels between the groups (P = 0.8).

Discussion

We observed impaired oxidant/antioxidant status in favor of oxidative stress in CIHF patients. Oxidative stress may be a key factor in the development of hypoalbuminemia in CIHF. Further studies are needed to establish the relationships among IMA, albumin, and redox balance in CIHF.     

Stem cells for the treatment of heart failure

Stem cell-based therapy is currently tested in several trials of chronic heart failure. The main question is to determine how its implementation could be extended to common clinical practice. To fill this gap, it is critical to first validate the hypothesis that the grafted stem cells primarily act by harnessing endogenous repair pathways. The confirmation of this mechanism would have three major clinically relevant consequences: (i) the use of cardiac-committed cells, since even though cells primarily act in a paracrine manner, such a phenotype seems the most functionally effective; (ii) the optimization of early cell retention, rather than of sustained cell survival, so that the cells reside in the target tissue long enough to deliver the factors underpinning their action; and (iii) the reliance on allogeneic cells, the expected rejection of which should only have to be delayed since a permanent engraftment would no longer be the objective. One step further, the long-term objective of cell therapy could be to use the cells exclusively for producing factors and then to only administer them to the patient. The production process would then be closer to that of a biological pharmaceutic, thereby facilitating an extended clinical use.     

Clinical effects of an optimised care program with telehealth in heart failure patients in a community hospital in the Netherlands

Background

Our hypothesis was that telehealth in combination with an optimised care program coordinated amongst care professionals in primary, secondary and tertiary care can achieve beneficial outcomes in heart failure. The objective was to evaluate the clinical effects of introduction of telehealth in an optimised care program in a community hospital in the north of the Netherlands.

Methods

We compared the number of unplanned admissions for heart failure in the year before and after adding telehealth to the optimised care program. Furthermore, blood pressure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were evaluated at baseline and 3, 6 and 12 months after telehealth. Quality of life and knowledge about the disease were regularly evaluated via surveys on the telehealth system.

Findings

The number of unplanned admissions for heart failure decreased from on average 1.29 to 0.31 admissions per year after telehealth introduction. Blood pressure decreased independent of medication and NT-proBNP levels improved as well. Quality of life increased during the telehealth intervention and disease knowledge remained high throughout the follow-up period. Unplanned admissions that remained after telehealth introduction could be accurately predicted at baseline by a multivariate regression model.     

Protective potential of resveratrol against oxidative stress and apoptosis in Batten disease lymphoblast cells

Batten disease (BD) is the most common form of a group of disorders called neuronal ceroid lipofuscinosis, which are caused by a CLN3 gene mutation. A variety of pathogenic lysosomal storage disorder mechanisms have been suggested such as oxidative stress, endoplasmic reticulum (ER) stress, and altered protein trafficking. Resveratrol, a stilbenoid found in red grape skin, is a potent antioxidant chemical. Recent studies have suggested that resveratrol may have a curative effect in many neurodegenerative diseases. Therefore, we investigated the activities of resveratrol at the levels of oxidative and ER stress and apoptosis factors using normal and BD lymphoblast cells. We report that the BD lymphoblast cells contained low-levels of superoxide dismutase-1 (SOD-1) due to the long-term stress of reactive oxygen species. However, when we treated the cells with resveratrol, SOD-1 increased to levels observed in normal cells. Furthermore, we investigated the expression of glucose-regulated protein 78 as an ER stress marker. BD cells underwent ER stress, but resveratrol treatment resolved the ER stress in a dose-dependent manner. We further demonstrated that the levels of apoptosis markers such as apoptosis induce factor, cytochrome c, and cleavage of poly (ADP)-ribose polymerase decreased following resveratrol treatment. Thus, we propose that resveratrol may have beneficial effects in patients with BD.     

Searching for biomarkers of heart failure in the mass spectra of blood plasma

We have developed a technique for analysing blood plasma using MALDI-MS with subsequent data analysis to identify significant and specific differences between heart failure (HF) patients and healthy individuals. A training dataset comprising 100 HF patients and 100 healthy individuals was used to search for biomarkers (m/z range 1000-10,000). EWP cartridges when used in tandem with microcon centrifugal filters were found to give the best results. A data management chain including event binning, background subtraction and feature extraction was developed to reduce the data, and statistical analysis was used to map feature intensities on to a common scale. Various mathematical approaches including a simple cumulative score, support vector machines (SVM) and genetic algorithms (GAs) were then used to combine the results from individual features and provide a robust classification algorithm. The SVM gave the most promising results (accuracy 95%, receiver operating characteristic (ROC) score of 0.997 using 18 selected features). Finally, a test dataset comprising a further 32 HF patients and 20 controls was used to verify that the 18 putative biomarkers and classification algorithms gave reliable predictions (accuracy 88.5%, ROC score 0.998).