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Increased presence of oxidized low-density lipoprotein in the left ventricular blood of subjects with cardiovascular disease.

ABSTRACT: OxidizedLDL(Ox-LDL) and oxidative stress have been implicated in both atherosclerosis and congestive heart failure (HF) development. Here, we tested whether Ox-LDLlevels in left ventricular blood (LVB) might differ from those of venous peripheral blood (PB), and whether the level might depend on cardiac function. We also tested whether theLDLmolecule is likely to have a longer residence time in the left ventricle ofHFsubjects with low ejection fraction (EF). The aim of this study was to determine Ox-LDLlevels, paraoxonase 1 (PON1) activity, and cholesterol efflux capacity (CEC) ofPBandLVB, and correlate these values withLVEF Sixty-oneHFpatients underwent preoperative transthoracic echocardiographic assessment of ventricular function.LVEFs were determined using Simpson's biplane technique.LVBandPBlevels of Ox-LDLwere determined, andPON1 activity and plasma cholesterol efflux capacity were measured. A significant increase in the levels of Ox-LDLinLVBwas noted as compared to levels inPB, even whenEFwas near normal. However, as ejection fraction decreased, the level of Ox-LDLinPBapproached that of theLVBPON1 activity and cholesterol efflux studies indicated increased oxidative stress inLVBand a decreased ability to promote cholesterol efflux from lipid-enriched macrophages. The results suggest thatLVBis more oxidatively stressed compared toPB, and thereforeLVtissue might be affected differently than peripheral tissues. We recently reported that brain natriuretic peptide (BNP), a marker forHF, is induced by Ox-LDL, so it is possible localized factors within theLVcould profoundly affect markers ofHF.

SUBMITTER: Aluganti Narasimhulu C

PROVIDER: S-EPMC4814879 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Increased presence of oxidized low-density lipoprotein in the left ventricular blood of subjects with cardiovascular disease.

Aluganti Narasimhulu Chandrakala C Litvinov Dmitry D Sengupta Bhaswati B Jones Danielle D Sai-Sudhakar Chittoor C Firstenberg Michael M Sun Benjamin B Parthasarathy Sampath S

Physiological reports 20160331 6

OxidizedLDL(Ox-LDL) and oxidative stress have been implicated in both atherosclerosis and congestive heart failure (HF) development. Here, we tested whether Ox-LDLlevels in left ventricular blood (LVB) might differ from those of venous peripheral blood (PB), and whether the level might depend on cardiac function. We also tested whether theLDLmolecule is likely to have a longer residence time in the left ventricle ofHFsubjects with low ejection fraction (EF). The aim of this study was to determin ...[more]

PMID: 27033448

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Project description:Apolipoproteins are associated with survival among patients on hemodialysis (HD), but these associations might be influenced by dysfunctional (oxidized) high-density lipoprotein (HDL). We assessed associations among apolipoproteins and oxidized HDL, mortality and cardiovascular disease (CVD) events in patients on HD. This prospective observational study examined 412 patients on prevalent HD. Blood samples were obtained before dialysis at baseline to measure lipids, apolipoproteins, oxidized LDL, oxidized HDL, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 at baseline, and HDL-C and hs-CRP were measured 12 months later. Patients were then prospectively followed-up (mean, 40 months) and all-cause mortality and composite CVD events were analyzed. Associations between variables at baseline and clinical outcome were assessed by Cox proportional hazards modeling (n = 412) and Cox hazards modeling with a time-varying covariate with HDL-C and hs-CRP (n = 369). Quartiles of apolipoproteins and oxidized HDL were not associated with all-cause mortality. However, Cox proportional hazards models with quartiles of each variable adjusted for confounders and hs-CRP or IL-6 identified apolipoprotein (apo)B-to-apoA-I ratio (apoB/apoA-I) and oxidized HDL, but not apoA-I or apoA-II, as independent risk factors for composite CVD events. These associations were confirmed by Cox proportional hazards modeling with time-varying covariates for hs-CRP. ApoB/apoA-I was independently associated with composite CVD events in 1-standard deviation (SD) increase-of-variables models adjusted for the confounders, oxidized HDL and hs-CRP. However, these associations disappeared from the model adjusted with IL-6 instead of hs-CRP, and oxidized HDL and IL-6 were independently associated with composite CVD events. Findings resembled those from Cox proportional hazards modeling using time-varying covariates with HDL-C adjusted with IL-6. In conclusion, both oxidized HDL and apoB/apoA-I might be associated with CVD events in patients on prevalent HD, while associations of apoB/apoA-I with CVD events differed between models of apoB/apoA-I quartiles and 1-SD increases, and were influenced by IL-6.

Project description:BACKGROUND:Quantification and visualisation of left ventricular (LV) blood flow is afforded by three-dimensional, time resolved phase contrast cardiovascular magnetic resonance (CMR 4D flow). However, few data exist upon the repeatability and variability of these parameters in a healthy population. We aimed to assess the repeatability and variability over time of LV 4D CMR flow measurements. METHODS:Forty five controls underwent CMR 4D flow data acquisition. Of these, 10 underwent a second scan within the same visit (scan-rescan), 25 returned for a second visit (interval scan; median interval 52 days, IQR 28-57 days). The LV-end diastolic volume (EDV) was divided into four flow components: 1) Direct flow: inflow that passes directly to ejection; 2) Retained inflow: inflow that enters and resides within the LV; 3) Delayed ejection flow: starts within the LV and is ejected and 4) Residual volume: blood that resides within the LV for >?2 cardiac cycles. Each flow components' volume was related to the EDV (volume-ratio). The kinetic energy at end-diastole (ED) was measured and divided by the components' volume. RESULTS:The dominant flow component in all 45 controls was the direct flow (volume ratio 38?±?4%) followed by the residual volume (30?±?4%), then delayed ejection flow (16?±?3%) and retained inflow (16?±?4%). The kinetic energy at ED for each component was direct flow (7.8?±?3.0 microJ/ml), retained inflow (4.1?±?2.0 microJ/ml), delayed ejection flow (6.3?±?2.3 microJ/ml) and the residual volume (1.2?±?0.5 microJ/ml). The coefficients of variation for the scan-rescan ranged from 2.5%-9.2% for the flow components' volume ratio and between 13.5%-17.7% for the kinetic energy. The interval scan results showed higher coefficients of variation with values from 6.2-16.1% for the flow components' volume ratio and 16.9-29.0% for the kinetic energy of the flow components. CONCLUSION:LV flow components' volume and their associated kinetic energy values are repeatable and stable within a population over time. However, the variability of these measurements in individuals over time is greater than can be attributed to sources of error in the data acquisition and analysis, suggesting that additional physiological factors may influence LV flow measurements.

Project description:Background and aimsAs the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease.MethodsTo answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo.ResultsConfirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries.ConclusionsWe identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.

Dataset Information

Increased presence of oxidized low-density lipoprotein in the left ventricular blood of subjects with cardiovascular disease.

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Increased presence of oxidized low-density lipoprotein in the left ventricular blood of subjects with cardiovascular disease.

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