Torcetrapib impairs endothelial function in hypertension

Aims A marked increase in HDL notwithstanding, the cholesterol ester transfer protein (CETP) inhibitor torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial. As underlying mechanisms remain elusive, the present study was designed to delineate potential off-target effects of torcetrapib. Methods and results Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib (100 mg/kg/day; SHR-T and WKY-T) or placebo (SHR-P and WKY-P) for 3 weeks. Blood pressure transiently increased during the first 3 days of torcetrapib administration in SHRs and returned to baseline thereafter despite continued drug administration. Acetylcholine-induced endothelium-dependent relaxations of aortic rings were markedly impaired, and endothelial nitric oxide synthase (eNOS) mRNA and protein were down-regulated after 3 weeks of torcetrapib treatment in SHR (P < 0.0001, <0.01, and <0.05, resp. vs. SHR-P). Torcetrapib reduced NO release in cultured aortic endothelial cells (P < 0.01 vs. vehicle-treated cells) and increased generation of reactive oxygen species in aortas of SHR-T (P < 0.05, vs. SHR-P). Vascular reactivity to endothelin-1 (ET-1) and aortic ET-1 tissue content were increased in SHR-T (P < 0.05 vs. SHR-P). Importantly, the ET-1 receptor A/B (ETA/B) antagonist bosentan normalized endothelial function in SHR-T (P < 0.05). Conclusion Torcetrapib induces a sustained impairment of endothelial function, decreases eNOS mRNA, protein as well as NO release, stimulates vascular ROS and ET production, an effect that is prevented by chronic ETA/B-receptor blockade. These unexpected off-target effects of torcetrapib need to be ruled out in the clinical development of novel CETP inhibitors, particularly before a large patient population at increased cardiovascular risk is exposed to these compound

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis

Aims Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. Methods and results Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-κB signalling pathway. Conclusion Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formatio

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis

Aims Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. Methods and results Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-kappaB signalling pathway. Conclusion Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation

Nutritional status in tricuspid regurgitation: implications of transcatheter repair

Aims To characterize the prevalence and clinical relevance of malnutrition in patients undergoing transcatheter tricuspid valve edge-to-edge repair (TTVR). Methods and results Overall, 86 consecutive patients (mean age 78 ± 7 years) with moderate-to-severe tricuspid regurgitation (TR) at prohibitive surgical risk were analysed. Mini Nutritional Assessment (MNA), quality of life assessment, 6-min walk test distance and laboratory analyses were performed before and 1 month after TTVR. A total of 43 patients (50%) underwent concomitant transcatheter mitral valve repair. According to MNA, 81 patients (94%) were malnourished or at risk of malnutrition before TTVR. Following TTVR, MNA improved in 64 patients (74%). As compared to patients without MNA improvement, patients with increased MNA score had greater reductions in TR [regurgitation volume −17.0 (interquartile range, IQR −25.0; −7.0) mL vs. −26.4 (IQR −40.3; −14.5) mL, P < 0.001] and inferior vena cava diameter. Only patients with increased MNA score displayed a decrease in N-terminal pro-brain natriuretic peptide levels [−320 (IQR −1294; 105) pg/mL vs. +708 (IQR −342; 2708) pg/mL, P = 0.009], improvements in cholinesterase levels (0.0 ± 11.9 μmoL/L vs. +10.9 ± 16.7 μmoL/L, P < 0.001) and renal function during follow-up. Beneficial effects on quality of life scores and 6-min walk test distance following TTVR were observed exclusively in patients with improvement in MNA. During a median follow-up of 6 months, patients with worsened MNA had an increased risk of death and rehospitalization for heart failure. Conclusion Nutritional impairment is common and of prognostic importance in patients undergoing TTVR. Hepatorenal function modestly improves after successful TTVR. Further study of extracardiac implications of TR-associated right heart failure is warranted to improve care in this vulnerable patient population

Cardiac output states in patients with severe functional tricuspid regurgitation: impact on treatment success and prognosis

Aims To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome. Methods and results A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centres. Patients were clustered according to k-means clustering into low [cardiac index (CI)  2.6 L/min/m2) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO clusters. Mortality rates were highest for patients in a low (24%) and high CO state (42%, log-rank P < 0.001). High CO state patients were characterized by larger inferior vena cava diameters (P = 0.003), reduced liver function, higher incidence of ascites (P = 0.006) and markedly reduced systemic vascular resistance (P < 0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (P = 0.01) and right ventricular dimensions (P < 0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO state patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low and high CO state patients. Conclusions Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome. Graphical Abstract Proposed mechanism of hypercirculatory tricuspid regurgitation. Tricuspid regurgitation related backward failure causes liver congestion and dysfunction with portal hypertension and reduced washout of vasoactive substances. Consequent splanchnic and peripheral vasodilatation alongside with reduced renal blood flow results in renin–angiotensin–aldosterone system (RAAS) activation and sympathetic overactivation. The sympathetic drive and volume retention lead to further capacitance depletion and volume overload, eventually resulting in a high cardiac output state, with limited preload reduction and prognostic benefit following transcatheter tricuspid valve repair. The alterations in the graph should be interpreted as simultaneous interaction rather than a timeline. Continuous lines indicate findings in the present study. Dashed lines express currently accepted mechanistical considerations. AP, alkaline phosphatase; γGT, gamma-glutamyl-transferase; RA, right atrium; RV, right ventricle

Approximation of mechanical properties of sintered materials with discrete element method

Sintering process is a key step in ceramic processing, which has strong influence on quality of final product. The final shape, microstructure and mechanical properties, e.g. density, heat conductivity, strength and hardness are depending on the sintering process. In order to characterize mechanical properties of sintered materials, in this contribution we present a microscale modelling approach. This approach consists of three different stages: simulation of the sintering process, transition to final structure and modelling of mechanical behaviour of sintered material with discrete element method (DEM). To validate the proposed simulation approach and to investigate products with varied internal structures alumina powder has been experimentally sintered at different temperatures. The comparison has shown that simulation results are in a very good agreement with experimental data and that the novel strategy can be effectively used for modelling of sintering process

Approximation of mechanical properties of sintered materials with discrete element method

Sintering process is a key step in ceramic processing, which has strong influence on quality of final product. The final shape, microstructure and mechanical properties, e.g. density, heat conductivity, strength and hardness are depending on the sintering process. In order to characterize mechanical properties of sintered materials, in this contribution we present a microscale modelling approach. This approach consists of three different stages: simulation of the sintering process, transition to final structure and modelling of mechanical behaviour of sintered material with discrete element method (DEM). To validate the proposed simulation approach and to investigate products with varied internal structures alumina powder has been experimentally sintered at different temperatures. The comparison has shown that simulation results are in a very good agreement with experimental data and that the novel strategy can be effectively used for modelling of sintering process

Approximation of mechanical properties of sintered materials with discrete element method

Sintering process is a key step in ceramic processing, which has strong influence on quality of final product. The final shape, microstructure and mechanical properties, e.g. density, heat conductivity, strength and hardness are depending on the sintering process. In order to characterize mechanical properties of sintered materials, in this contribution we present a microscale modelling approach. This approach consists of three different stages: simulation of the sintering process, transition to final structure and modelling of mechanical behaviour of sintered material with discrete element method (DEM). To validate the proposed simulation approach and to investigate products with varied internal structures alumina powder has been experimentally sintered at different temperatures. The comparison has shown that simulation results are in a very good agreement with experimental data and that the novel strategy can be effectively used for modelling of sintering process