Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure.

The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8 days after coronary ligation) and delayed 3-day (starting 47 days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25 mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure-volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure-volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.

Merabet N ，Bellien J ，Glevarec E ，Nicol L ，Lucas D ，Remy-Jouet I ，Bounoure F ，Dreano Y ，Wecker D ，Thuillez C ，Mulder P ... -  《-》

Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

Fang Y ，Debunne M ，Vercauteren M ，Brakenhielm E ，Richard V ，Lallemand F ，Henry JP ，Mulder P ，Thuillez C ... -  《-》

Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.

Mulder P ，Barbier S ，Chagraoui A ，Richard V ，Henry JP ，Lallemand F ，Renet S ，Lerebours G ，Mahlberg-Gaudin F ，Thuillez C ... -  《-》

Reduced cardiac remodelling and prevention of glutathione deficiency after omega-3 supplementation in chronic heart failure.

n-3 polyunsaturated fatty acids (omega-3) supplementation is associated with reduced cardiovascular mortality and post-infarction death. However, the impact of omega-3 supplementation in congestive heart failure (CHF) is still unknown. This study assesses the effects of omega-3 supplementation on left ventricular (LV) function and remodelling. We assessed, in rats with CHF induced by left coronary ligation, the effects of a 1-week and a 12-week supplementation with omega-3 (450 mg/kg per day) on LV hemodynamics, function and structure. Chronic omega-3 reduces total peripheral resistance due to an increase in cardiac output without modification of arterial pressure. Only chronic omega-3 reduces LV end-diastolic pressure and LV relaxation constant. Moreover, chronic omega-3 decreases LV systolic and diastolic diameters, LV weight and collagen density. Acute and chronic omega-3 increase LV γ-glutamyl-cysteine synthetase and oppose glutathione deficiency resulting in a reduction of myocardial oxidized glutathione. In experimental CHF, long-term omega-3 supplementation improves LV hemodynamics and function and prevents LV remodelling and glutathione deficiency. The latter might be one of the mechanisms involved, but whether other mechanism, independent of myocardial redox 'status', such as reduced inflammation, are implicated remains to be confirmed.

Fang Y ，Favre J ，Vercauteren M ，Laillet B ，Remy-Jouet I ，Skiba M ，Lallemand F ，Dehaudt C ，Monteil C ，Thuillez C ，Mulder P ... -  《-》

Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure.

Mellin V ，Isabelle M ，Oudot A ，Vergely-Vandriesse C ，Monteil C ，Di Meglio B ，Henry JP ，Dautreaux B ，Rochette L ，Thuillez C ，Mulder P ... -  《EUROPEAN HEART JOURNAL》