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During the last decade, considerable interest has been focused on the potential role of oxygen free radical generation in the pathophysiology of chronic congestive heart failure. Oxidative stress has been demonstrated in different animal models of congestive heart failure: volume overload, pressure overload, myocardial infarction, and adriamycin-induced cardiomyopathy. In contrast with animal studies, human studies are less convincing given that most of the traditional methods used to assess oxidative stress in the clinical setting are non-specific or inaccurate.1
A novel family of prostaglandin F2 isomers, called F2-isoprostanes, produced in vivo by a free radical peroxidation of arachidonic acid, has recently been described.2 Isoprostaglandin F2α type III, formerly known as 8-iso-prostaglandin F2α, is a biochemically stable F2-isoprostane, formed by direct free radical peroxidation of arachidonic acid of cell membranes or circulating low density lipoprotein.2 Its quantification in tissues and biological fluids has been suggested to be a reliable measure of oxidant injury in vivo. Indeed, urinary excretion of this compound has been well characterised and is currently used as an index of lipid peroxidation in human diseases. A recent study has shown that concentrations of isoprostaglandin F2α type III were increased in pericardial fluid of patients with symptomatic heart failure.3 However, urinary measurements may be of more clinical use for follow up studies. The purpose of the present study was to investigate urinary isoprostaglandin F2α type III formation as an index of lipid peroxidation in patients suffering from severe heart failure.
Twenty five consecutive patients suffering from heart failure were included between April and July 1999. Patients were referred before heart transplantation or for a left ventricular failure episode. Patients were matched with 25 healthy volunteers (22 men, 3 women, median age 56 years (range 25–73 years), 11 smokers). The criterion for admission into the study was a left ventricular ejection fraction < 45%. Criteria for exclusion were severe valve disease and congenital heart disease. Two subgroups of patients were identified: seven patients with chronic heart failure secondary to ischaemic heart disease—that is, documented myocardial infarction and/or angiographically demonstrated coronary artery disease; and 18 patients with idiopathic dilated cardiomyopathy, with angiographically normal coronary arteries. The clinical characteristics of the patients are depicted in table 1.
This study conformed to the principles outlined in the declaration of Helsinki.
Complete M mode (one dimensional) and cross sectional (two dimensional) echocardiographic examinations were performed in all patients. Left ventricular end diastolic and end systolic volumes were measured from the parasternal long and short axis views, and the ejection fraction calculated. Exercise tests were performed two months after the last episode of acute left ventricular failure in 14 patients. Oxygen consumption (Vo 2) was determined during the stress test by a cycle to cycle method (Medical Graphics).Vo 2 measurements were expressed as a percentage of the predicted normal values for sedentary adults (Vo 2max).
Urine samples were collected during hospitalisation between 8 and 10 am in polyethylene tubes (20 ml), after which they were transferred to the laboratory, aliquoted, and stored at −20°C. Samples were extracted using a method derived from that previously described by Nourooz-Zadeh.4 Isoprostaglandin F2α type III (8-isoprostane F2α) and 11-dehydro-thromboxane B2 concentrations were determined by enzyme immunoassay (Cayman, Ann Arbor, USA). The results obtained in pg/ml were standardised versus urinary creatinine concentrations. Final results were expressed as pmol/mmol of creatinine.
Continuous variables were expressed as means with standard deviations in parentheses. Analysis of variance (Kruskal-Wallis method, followed by Mann-Whitney U test) was used for statistical comparisons. Regression analyses were performed using the Spearman rank correlation test. Values of p < 0.05 were considered significant.
Urinary excretion of isoprostaglandin F2α type III was significantly higher (p < 0.0001) in patients suffering from severe heart failure compared with age and sex matched controls: 259 (191) versus 110 (36) pmol/mmol creatinine (fig 1). Concentrations of isoprostaglandin F2α type III in New York Heart Association (NYHA) class IV patients were significantly higher (p < 0.05) than those in NYHA class II and III: 426 (296) versus 199 (83) and 214 (139) pmol/mmol, respectively (fig 1). Urinary excretion of 11-dehydro-thromboxane B2 was significantly higher (p < 0.001) in patients compared with controls: 317 (242) versus 119 (64) pmol/mmol. However, no significant differences were found between the different functional classes.
Urinary concentrations of isoprostaglandin F2α type III were not correlated to left ventricular end diastolic diameter or to left ventricular ejection fraction. A difference between ischaemic and idiopathic dilated cardiomyopathy subgroups was not observed. There was a non-significant trend towards a correlation between isoprostaglandin F2α type III concentrations and Vo 2max. A significant correlation was found between isoprostaglandin F2α type III and 11-dehydro-thromboxane B2 urinary concentrations (r = 0.64, p < 0.001), suggesting a link between lipid peroxidation and platelet activation.
No significant differences in isoprostaglandin F2α type III urinary concentrations were found between patients on aspirin versus those not on aspirin (241 (118) v 271 (230) pmol/mmol respectively), or between patients on carvedilol versus those not on carvedilol (256 (140) v260 (220) pmol/mmol, respectively).
In our study, a significant increase in isoprostaglandin F2α type-III concentrations was found in the urine samples from patients with severe heart failure compared with controls, independent of cardiac failure aetiology. Consistent with a previous study on pericardial concentrations of isoprostaglandin F2α type III,3 we found a correlation between the functional classes and the urinary concentration. Furthermore, there was a trend towards a correlation between isoprostaglandin F2α type III concentrations and Vo 2max. These results suggest that oxidative stress is correlated with the progression of heart failure and with the deterioration of functional capacity. However, it remains undetermined whether lipid peroxidation plays a pathophysiological role in the evolution of cardiac failure, or if isoprostaglandin F2αtype III only reflects tissue damage in patients with heart failure. It has been suggested that free radical generation may play a role in both contractile dysfunction and structural damage to the myocardium. Furthermore, isoprostaglandin F2α type III has been shown to be a potent vasoconstrictor in animal and human vascular beds. As a consequence, isoprostaglandin F2α type III may contribute to the increased peripheral and pulmonary vascular tone observed in cardiac failure and thus contribute to the functional deterioration.
Urinary 11-dehydro-thromboxane B2—an index of thromboxane synthesis in vivo—was increased in heart failure patients, suggesting enhanced platelet activation. This finding is in accordance with those of a recent study, in which both soluble and platelet bound P selecting concentrations were higher in patients with heart failure compared with controls.5 The correlation observed between 11-dehydro-thromboxane B2 and isoprostaglandin F2α type III excretion is consistent with a link between enhanced lipid peroxidation and platelet activation in heart failure.
An important advantage of isoprostaglandin F2α type III measurement in urine over other methods is that it is non-invasive, reproducible, and may be repeated over time. Several therapeutic approaches including carvedilol, amiodarone, and vitamin E have recently been shown to protect cardiac myocytes against oxidative injury in vitro. The results of the present study provide a rationale for clinical trials based on measurements of F2-isoprostanes to assess the antioxidant properties of these drugs in heart failure. Indeed, such an approach has recently been described in hypercholesterolaemia and diabetes. In both studies, vitamin E supplementation induced dose dependent reductions in F2-isoprostanes concentrations.
The present study shows that severe heart failure is associated with an increase in urine concentrations of isoprostaglandin F2αtype III, an index of lipid peroxidation. Urinary measurement of F2-isoprostanes may provide a non-invasive biochemical end point for antioxidant therapeutics investigations in heart failure.
Isoprostaglandin F2α, also known as isoprostaglandin F2α type III, is a member of a group of prostanoids called F2-isoprostanes. These are produced as a result of cell membrane lipid peroxidation mediated by reactive oxygen species (free radicals). This small study reports that urinary excretion of isoprostaglandin F2α can be used to assess the extent of oxidative stress in heart failure patients and that urinary concentrations correlate with the functional severity of disease. The technique may have potential for development as a non-invasive quantitative tool for monitoring response to treatment in patients with heart failure.
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