The routine use of mechanical circulatory support during lung transplantation (LTx) is still controversial. The use of prophylactic human albumin (HA) or hypertonic sodium lactate (HSL) prime in ...mechanical circulatory support during LTx could prevent ischemia−reperfusion (IR) injuries and pulmonary endothelial dysfunction and thus prevent the development of pulmonary graft dysfunction. The objective was to investigate the impact of cardiopulmonary bypass (CPB) priming with HA and HSL compared to a CPB prime with Gelofusine (GF) on pulmonary endothelial dysfunction in a lung IR rat model. Rats were assigned to four groups: IR-CPB-GF group, IR-CPB-HA group, IR-CPB-HSL group and a sham group. The study of pulmonary vascular reactivity by wire myograph was the primary outcome. Glycocalyx degradation (syndecan-1 and heparan) was also assessed by ELISA and electron microscopy, systemic and pulmonary inflammation by ELISA (IL-1β, IL-10, and TNF-α) and immunohistochemistry. Clinical parameters were evaluated. We employed a CPB model with three different primings, permitting femoral−femoral assistance with left pulmonary hilum ischemia for IR. Pulmonary endothelium-dependent relaxation to acetylcholine was significantly decreased in the IR-CPB-GF group (11.9 ± 6.2%) compared to the IR-CPB-HA group (52.8 ± 5.2%, p < 0.0001), the IR-CPB-HSL group (57.7 ± 6.3%, p < 0.0001) and the sham group (80.8 ± 6.5%, p < 0.0001). We did not observe any difference between the groups concerning glycocalyx degradation, and systemic or tissular inflammation. The IR-CPB-HSL group needed more vascular filling and developed significantly more pulmonary edema than the IR-CPB-GF group and the IR-CPB-HA group. Using HA as a prime in CPB during Ltx could decrease pulmonary endothelial dysfunction’s IR-mediated effects. No effects of HA were found on inflammation.
Background Changes in arterial wall viscosity, which dissipates the energy stored within the arterial wall, may contribute to the beneficial effect of heart rate (HR) reduction on arterial stiffness ...and cardiovascular coupling. However, it has never been assessed in humans and could be altered by aging. We evaluated the effect of a selective HR-lowering agent on carotid arterial wall viscosity and the impact of aging on this effect. Methods and Results This randomized, placebo-controlled, double-blind, crossover study performed in 19 healthy volunteers evaluated the effects of ivabradine (5 mg BID, 1-week) on carotid arterial wall viscosity, mechanics, hemodynamics, and cardiovascular coupling. Arterial wall viscosity was evaluated by the area of the hysteresis loop of the pressure-lumen cross-sectional area relationship, representing the energy dissipated (W
), and by the relative viscosity (W
/W
), with W
representing the elastic energy stored. HR reduction by ivabradine increased W
and W
whereas W
/W
remained stable. In middle-aged subjects (n=11), baseline arterial stiffness and cardiovascular coupling were less favorable, and W
was similar but W
and therefore W
/W
were lower than in youth (n=8). HR reduction increased W
/W
in middle-aged but not in young subjects, owing to a larger increase in W
than W
. These results were supported by the age-related linear increase in W
/W
after HR reduction (
=0.009), explained by a linear increase in W
. Conclusion HR reduction increases arterial wall energy dissipation proportionally to the increase in W
, suggesting an adaptive process to bradycardia. This mechanism is altered during aging resulting in a larger than expected energy dissipation, the impact of which should be assessed. Registration URL: https://www.clinicaltrials.gov; Unique identifier: 2015/077/HP. URL: https://www. eudract.ema.europa.eu; Unique identifier: 2015-002060-17.
Whether a cytochrome P-450 (CYP)-related endothelium-derived hyperpolarizing factor (EDHF), acting through calcium-activated potassium (K(Ca)) channels, interacts with nitric oxide (NO) to regulate ...the basal diameter of human peripheral conduit arteries is unexplored in vivo. Radial artery diameter (echo tracking) and blood flow (Doppler) were measured, after oral aspirin (500 mg), in eight healthy volunteers during local infusion for 8 min of tetraethylammonium chloride (TEA; 9 micromol/min), as K(Ca) channel inhibitor, and fluconazole (0.4 micromol/min), as CYP inhibitor, alone and in combination with N(G)-monomethyl-L-arginine (L-NMMA; 8 micromol/min), as endothelial NO synthase inhibitor. Endothelium-independent dilatation was assessed by using sodium nitroprusside (SNP). Radial diameter was unaffected by L-NMMA (0.4 +/- 0.9%) and fluconazole (-1.6 +/- 0.8%) but was decreased by TEA (-5.0 +/- 1.0%), L-NMMA + fluconazole (-5.3 +/- 0.5%), and L-NMMA + TEA (-9.9 +/- 1.3%). These effects are still significant even when the concomitant decreases in blood flow induced by L-NMMA (-24 +/- 4%), TEA (-21 +/- 3%), L-NMMA + fluconazole (-26 +/- 5%), and L-NMMA + TEA (-35 +/- 4%) were taken as covariate into analysis. Conversely, fluconazole alone slightly but not significantly increased radial flow (13 +/- 6%). L-NMMA alone or with TEA and with fluconazole enhanced radial artery dilatation to SNP, whereas TEA and fluconazole alone did not modify this response. These results confirm in humans the involvement of NO and K(Ca) channels in the regulation of basal conduit artery diameter. Moreover, the synergistic effect of combined inhibition of NO synthesis and CYP on the decrease in radial diameter in the absence of such effect after L-NMMA and fluconazole alone unmasks the role of CYP in this regulation and shows the presence of an interaction between NO and a CYP-related EDHF to maintain peripheral conduit artery diameter in vivo. Furthermore, the higher vasoconstrictor effect of TEA compared with fluconazole suggests that different K(Ca) channel-dependent hyperpolarizing mechanisms could exist in conduit arteries.
Diabetic CVD--soluble epoxide hydrolase as a target Lorthioir, Aurelien; Guerrot, Dominique; Joannides, Robinson ...
Cardiovascular & hematological agents in medicinal chemistry
10, Številka:
3
Journal Article
Recenzirano
The incidence of cardiovascular diseases remains high in diabetic patients despite the optimization of blood glucose control and the therapeutic management of risk factors. One emerging promising ...pharmacological approach that may help to prevent the development of diabetic cardiovascular complications is to improve endothelial function through the restoration of the bioavailability of epoxyeicosatrienoic acids (EETs). EETs are crucial eicosanoid signaling molecules synthesized by cytochrome P450 epoxygenases in the vascular endothelium and in pancreatic islets. EETs promote vasodilatation and display attractive anti-inflammatory and anti-aggregating actions together with potent effects on insulin release and sensitivity. In animal models of insulin-resistance and diabetes, a decrease in EET availability has been reported, and is a deleterious mechanism that probably contributes to multiple metabolic, cardiovascular and renal disorders in this setting. Moreover, increasing experimental evidence suggest that the use of soluble epoxide hydrolase (sEH) inhibitors, which prevent EET degradation, is a promising pharmacological approach to prevent endothelial dysfunction and to protect against target organ damage in metabolic diseases. This review presents evidence that the EET pathway is disturbed from the early stages of metabolic diseases, and analyzes the potential contribution of EETs impairment to the progression of cardiovascular diseases associated with diabetes. Pathophysiological and therapeutic perspectives are thereafter discussed, including the necessity to demonstrate the role of EET pathway alterations in endothelial dysfunction associated with diabetes in human, and the interest of sEH inhibitors to prevent the development of diabetic cardiovascular complications, with the expected result of improving patients' health.
Epoxyeicosatrienoic acids (EETs) are vasodilating lipid mediators metabolized into dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase. We aimed to develop a LC-MS/MS method to ...quantify EETs and DHETs in human plasma and monitored their levels during vascular endothelial stimulation. Plasma samples, collected from 14 healthy and five hypertensive subjects at baseline and during radial artery endothelium-dependent flow-mediated dilatation, were spiked with internal standards. Lipids were then extracted by a modified Bligh and Dyer method and saponified to release bound EETs and DHETs. Samples were purified by a second liquid–liquid extraction and analyzed by LC-MS/MS. The assay allowed identification of (±)8(9)-epoxy-5Z,11Z,14Z-eicosatrienoic acid (8,9-EET); (±)11(12)-epoxy-5Z,8Z,14Z-eicosatrienoic acid (11,12-EET); (±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-EET); (±)8,9-dihydroxy-5Z,11Z,14Z-eicosatrienoic acid (8,9-DHET); (±)11,12-dihydroxy-5Z,8Z,14Z-eicosatrienoic acid (11,12-DHET); and (±)14,15-dihydroxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-DHET). (±)5(6)-epoxy-5Z,11Z,14Z-eicosatrienoic acid (5,6-EET) was virtually undetectable due to its chemical instability. The limits of quantification were 0.25 ng/mL for DHETs and 0.5 ng/mL for EETs. Intra- and inter-assay variations ranged from 1.6 to 13.2%. Heating induced a similar increase in 8,9-EET, 11,12-EET, and 14,15-EET levels and in corresponding DHET levels in healthy but not in hypertensive subjects. We validated a sensitive LC-MS/MS method for measuring simultaneously plasma EET and DHET regioisomers in human plasma and showed its interest for assessing endothelial function.
Circulating endothelial progenitor cells (EPCs) were first described in 1997 by Asahara et al. as "putative endothelial cells" from human peripheral blood. The study of endothelial progenitors is ...also intensifying in several pathologies associated with endothelial damage, including diabetes, myocardial infarction, sepsis, pulmonary arterial hypertension, obstructive bronchopneumopathy and transplantation. EPCs have been studied in several autoimmune diseases with endothelial involvement such as systemic lupus erythematosus, thrombotic thrombocytopenic purpura, antineutrophil cytoplasmic antibodies, vasculitis, rheumatoid arthritis, Goujerot-Sjögren and antiphospholipid syndrome. Factors involved in endothelial damage are due to overexpression of pro-inflammatory cytokines and/or autoantibodies. Management of these pathologies, particularly the long-term use of glucocorticoids and methotrexate, promote atherosclerosis. A lack of standardized assessment of the number and function of EPCs represents a serious challenge for the use of EPCs as prognostic markers of cardiovascular diseases (CVD). The objective of this review was to describe EPCs, their properties and their involvement in several autoimmune diseases.
Links have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ damage are not well known in ...humans. The aim of this study was to explore whether ERS explains lung damage volume (LDV) among COVID-19 patients admitted to the intensive care unit (ICU).IntroductionLinks have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ damage are not well known in humans. The aim of this study was to explore whether ERS explains lung damage volume (LDV) among COVID-19 patients admitted to the intensive care unit (ICU).We conducted a single-center retrospective study (ancillary analysis of a prospective cohort) including severe COVID-19 ICU patients who had a chest computed tomography (CT) scan 24 h before/after admission to assess LDV. We performed two multivariate linear regression models to identify factors associated with plasma levels of 78 kDa-Glucose-Regulated Protein (GRP78; ERS marker) and Interleukin-6 (IL-6; inflammation marker) at admission.Materials and methodsWe conducted a single-center retrospective study (ancillary analysis of a prospective cohort) including severe COVID-19 ICU patients who had a chest computed tomography (CT) scan 24 h before/after admission to assess LDV. We performed two multivariate linear regression models to identify factors associated with plasma levels of 78 kDa-Glucose-Regulated Protein (GRP78; ERS marker) and Interleukin-6 (IL-6; inflammation marker) at admission.Among 63 patients analyzed, GRP78 plasma level was associated with LDV in both multivariate models (β = 22.23 4.08;40.38; p = 0.0179, β = 20.47 0.74;40.20; p = 0.0423) but not with organ failure (Sequential Organ Failure Assessment (SOFA) score) at admission (r = 0.03 -0.22;0.28; p = 0.2559). GRP78 plasma level was lower among ICU survivors (1539.4 1139.2;1941.1 vs. 1714.2 1555.2;2579.1 pg./mL. respectively; p = 0.0297). IL-6 plasma level was associated with SOFA score at admission in both multivariate models (β = 136.60 65.50;207.70; p = 0.0003, β = 193.70 116.60;270.90; p < 0.0001) but not with LDV (r = 0.13 -0.14;0.39; p = 0.3219). IL-6 plasma level was not different between ICU survivors and non-survivors (12.2 6.0;43.7 vs. 30.4 12.9;69.7 pg./mL. respectively; p = 0.1857). There was no correlation between GRP78 and IL-6 plasma levels (r = 0.13 -0.13;0.37; p = 0.3106).ResultsAmong 63 patients analyzed, GRP78 plasma level was associated with LDV in both multivariate models (β = 22.23 4.08;40.38; p = 0.0179, β = 20.47 0.74;40.20; p = 0.0423) but not with organ failure (Sequential Organ Failure Assessment (SOFA) score) at admission (r = 0.03 -0.22;0.28; p = 0.2559). GRP78 plasma level was lower among ICU survivors (1539.4 1139.2;1941.1 vs. 1714.2 1555.2;2579.1 pg./mL. respectively; p = 0.0297). IL-6 plasma level was associated with SOFA score at admission in both multivariate models (β = 136.60 65.50;207.70; p = 0.0003, β = 193.70 116.60;270.90; p < 0.0001) but not with LDV (r = 0.13 -0.14;0.39; p = 0.3219). IL-6 plasma level was not different between ICU survivors and non-survivors (12.2 6.0;43.7 vs. 30.4 12.9;69.7 pg./mL. respectively; p = 0.1857). There was no correlation between GRP78 and IL-6 plasma levels (r = 0.13 -0.13;0.37; p = 0.3106).Among severe COVID-19 patients, ERS was associated with LDV but not with systemic inflammation, while systemic inflammation was associated with organ failure but not with LDV.ConclusionAmong severe COVID-19 patients, ERS was associated with LDV but not with systemic inflammation, while systemic inflammation was associated with organ failure but not with LDV.
This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to ...dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.
Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.
These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.
The length of stay (LOS) after transcatheter aortic valve implantation (TAVI) remains extremely variable whereas early discharge has been shown to be feasible and safe. The study objective was to ...evaluate the efficacy and safety of an intervention aimed at reducing LOS after transfemoral TAVI.
FAST-TAVI II is a prospective, multicentre, cluster, randomized, controlled study including patients with severe symptomatic aortic stenosis, who had transfemoral TAVI. The intervention consisted in a dedicated training programme to implement 10 quality of care measures to reduce LOS with an implementation phase of eight weeks. The primary endpoint was the proportion of patients discharged early within 3 days. Secondary endpoints included: LOS, 30-day mortality and 30-day incidence of readmission for cardiovascular events.
During the study period, 969 patients were enrolled in the intervention group and 860 patients in the control group. Mean age was 81.9 ± 6.6 years and mean EuroSCORE II was 4.4 ± 4.5%. Early discharge was achieved in 563 (58.1%) patients in the intervention group vs. 364 (42.3%) patients in the control group (P < .0001). Median LOS was significantly reduced in the intervention group compared to the control group 3 (IQR: 3) vs. 4 days (IQR: 3), P < .0001. Thirty-day mortality was low and similar in the two groups (0.5% vs. 0.9%, P = .30), as were 30-day readmissions (4.6% vs. 2.8%, P = .28).
The intervention was simple and fast to implement, and was effective and safe to reduce LOS and increase the proportion of patients discharged early after TAVI (NCT04503655).
PDF
