Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease

Background

Patients with end-stage renal disease (ESRD) show a high prevalence of cardiovascular disease with arterial stiffness, atherosclerosis and endothelial dysfunction, leading to increased morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) exhibits proinflammatory and proatherogenic functions and has recently emerged as a major regulator of atherogenesis. Studies examining the relationship between circulating MIF levels and vascular dysfunction in this high-risk population do not exist.

Methods

In patients with ESRD (n = 39) and healthy controls (n = 16) we assessed endothelial function by flow-mediated dilation of the brachial artery and arterial stiffness (augmentation pressure, augmentation index and pulse pressure) using applanation tonometry. High-sensitive Troponin and subendocardial viability ratio were determined to assess myocardial injury.

Results

Patients with ESRD had impaired endothelial function and higher plasma MIF levels. MIF levels negatively correlated with endothelial function (r = − 0.345, P = 0.031) and positively with arterial stiffness indices in patients with ESRD (pulse pressure r = − 0.374, P = 0.019 and augmentation pressure r = − 0.423, P = 0.025). In multivariate regression models besides age, gender, weight, and heart rate, MIF was an independent predictor for arterial stiffness. Impact on myocardial end-organ damage was reflected by correlation with high-sensitive Troponin I (r = 0.43, P = 0.009).

Conclusion

Our findings show that high MIF plasma levels are associated with diminished endothelial function and arterial stiffness and are correlated with myocardial injury. Further studies are necessary to investigate whether modulation of MIF might have an impact on atherosclerotic disease in this high-risk population.     

Evidence for in vivo transport of bioactive nitric oxide in human plasma

Although hitherto considered as a strictly locally acting vasodilator, results from recent clinical studies with inhaled nitric oxide (NO) indicate that NO can exert effects beyond the pulmonary circulation. We therefore sought to investigate potential remote vascular effects of intra-arterially applied aqueous NO solution and to identify the mechanisms involved. On bolus application of NO into the brachial artery of 32 healthy volunteers, both diameter of the downstream radial artery and forearm blood flow increased in a dose-dependent manner. Maximum dilator responses were comparable to those after stimulation of endogenous NO formation with acetylcholine and bradykinin. Response kinetics and pattern of NO decomposition suggested that despite the presence of hemoglobin-containing erythrocytes, a significant portion of NO was transported in its unbound form. Infusion of NO (36 micromol/min) into the brachial artery increased levels of plasma nitroso species, nitrite, and nitrate in the draining antecubital vein (by < 2-fold, 30-fold, and 4-fold, respectively), indicative of oxidative and nitrosative chemistry. Infused N-oxides were inactive as vasodilators whereas S-nitrosoglutathione dilated conduit and resistance arteries. Our results suggest that NO can be transported in bioactive form for significant distances along the vascular bed. Both free NO and plasma nitroso species contribute to the dilation of the downstream vasculature.     

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double–Blind,Randomized, Placebo–Controlled Trial

Background and objectives

Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD.

Design, setting, participants, & measurements

We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics.

Results

CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD–induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01).

Conclusions

Dietary CF ingestion mitigates acute HD–induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.     

Health management as global challenge

Background

A hopeful journey into health was celebrated during the 19th World Conference of the International Union of Health Promotion and Education (IUHPE) initiated together with the Canadian Consortium for Health Promotion Research (CCHPR) from 10 to 15 June 2007 in Vancouver, Canada.

Aims

One of the main goals of this conference was to assess and determine the relevance of the Ottawa Charta-the historical document that was adopted in 1986 by an international World Health Organisation (WHO) conference-in the 21st century. These aims are reflected in the present work.

Methods

To enable a systematic transformation for reducing worldwide health inequities, different main topics were focussed on during the conference and are reflected on the basis of the current literature.

Results

Four main aspects are the focus: (1) creating supporting environments for health, (2) building healthy public policy, (3) strengthening community action and developing personal skills and (4) reorienting health systems. The outlines presented in this reflection provide a brief summary of important strategic directions through which networks of professionals and institutions can positively and constructively contribute to reducing health inequalities within and between countries in the world created by social, political, economic and environmental determinants. Therefore, several intersectoral future activities focussing on education e.g. in schools, workplaces, the setting of the family or even the hospital need to be performed.

Conclusion

Thus, health management is expected to join disease management as an integral part of future health care concepts.     

Regulation of nerve growth factor in the heart: The role of the calcineurin-NFAT pathway

A heightened sympathetic tone accelerates the development of lethal arrhythmias after myocardial infarction (MI) and the progression of heart failure (HF). Cardiomyocytes control their local neural milieu by expression of nerve growth factor (NGF), which triggers sympathetic neural growth (sympathetic nerve sprouting: SNS). The molecular mechanisms that regulate NGF expression are largely unknown. During HF or MI the myocytes are exposed to increased mechanical load and adrenergic stimulation. Both stimuli induce myocyte hypertrophy. The angiotensin-II-calcineurin-NFAT (nuclear factor of activated t-cells) pathway is a well characterized signaling cascade in the pathogenesis of myocyte hypertrophy. The present study aims to investigate the molecular mechanisms by which mechanical stretch and/or alpha-1-adrenergic stimulation affect NGF expression in neonatal rat ventricular myocytes. Both stimuli resulted in a down-regulation of NGF gene and protein expression. Angiotensin-II type 1 receptor blockade with losartan blunted the stretch-induced NGF down-regulation. Specific calcineurin inhibition with cyclosporine A and FK506 or NFAT inhibition with 11R-VIVIT reversed the stretch or alpha-1-adrenergic induced decrease of NGF. Calcineurin over-expression increased NFAT-DNA binding activity and decreased NGF expression. The magnitude of NGF decrease was sufficient to reduce neurite outgrowth of cultured sympathetic neurons. In conclusion, mechanical stretch and alpha-1-adrenergic stimulation contribute to a decrease of cardiomyocyte NGF expression via the calcineurin-NFAT pathway. To evaluate if the calcineurin-NFAT is critically involved in the pathogenesis of SNS further in-vivo studies in models of HF and MI are required. Nevertheless, the calcineurin-NFAT pathway may provide promising starting points for new pharmacological strategies to prevent SNS in the heart.     

Positive effects of nitric oxide on left ventricular function in humans.

AIMS: The myocardial effect of tonically released nitric oxide (NO) in humans is still not known. We tested the hypothesis that low-dose NO exerts positive effects on left ventricular (LV) function. METHODS AND RESULTS: Twelve healthy volunteers, 26+/-4 years, were enrolled in this study. Magnetic resonance imaging was used to precisely measure the direct effects of NO on stroke volume index (SVI). The NO pool was monitored by chemiluminescence. We reduced endogenous NO levels with intravenous infusion of the NO synthase-inhibitor N(G)-monomethyl-l-arginine. Replenishment of the NO pool was achieved with the NO donor S-nitrosoglutathione (GSNO) (0.5 micromol iv). To differentiate load-dependent from the direct effects of NO on LV function, changes in SVI in response to GSNO were compared with changes in the NO-independent vasodilator dihydralazine (2.5 mg iv) at matched arterial pressure and heart rate. Inhibition of NO synthesis was followed by reduction in SVI. Subsequent replenishment of the circulating NO with GSNO significantly increased SVI (39+/-8 to 54+/-7 mL m(-2); P=0.001), whereas no significant changes were observed with the NO-independent vasodilator dihydralazine (39+/-8 to 46+/-8 mL m(-2); P=0.0626). CONCLUSION: Inhibition of endogenous NO release reduces, whereas replenishment with exogenous NO increases LV function, pointing towards a positive effect of tonically released NO on LV function in healthy humans.