Ursolic Acid's Alluring Journey: One Triterpenoid vs. Cancer Hallmarks.

Cancer is a multifactorial disease characterized by various hallmarks, including uncontrolled cell growth, evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, among others. Traditional cancer therapies often target specific hallmarks, leading to limited efficacy and the development of resistance. Thus, there is a growing need for alternative strategies that can address multiple hallmarks concomitantly. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, has recently emerged as a promising candidate for multitargeted cancer therapy. This review aims to summarize the current knowledge on the anticancer properties of UA, focusing on its ability to modulate various cancer hallmarks. The literature reveals that UA exhibits potent anticancer effects through diverse mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of angiogenesis, inhibition of metastasis, and modulation of the tumor microenvironment. Additionally, UA has demonstrated promising activity against different cancer types (e.g., breast, lung, prostate, colon, and liver) by targeting various cancer hallmarks. This review discusses the molecular targets and signaling pathways involved in the anticancer effects of UA. Notably, UA has been found to modulate key signaling pathways, such as PI3K/Akt, MAPK/ERK, NF-κB, and Wnt/ß-catenin, which play crucial roles in cancer development and progression. Moreover, the ability of UA to destroy cancer cells through various mechanisms (e.g., apoptosis, autophagy, inhibiting cell growth, dysregulating cancer cell metabolism, etc.) contributes to its multitargeted effects on cancer hallmarks. Despite promising anticancer effects, this review acknowledges hurdles related to UA's low bioavailability, emphasizing the need for enhanced therapeutic strategies.

Association of calcium density in the thoracic aorta with risk factors and clinical events.

OBJECTIVES: In the ascending aorta, calcification density was independently and inversely associated with cardiovascular disease (CVD) risk prediction. Until now, the density of thoracic aorta calcium (TAC) was estimated as the Agatston score divided by the calcium area (DAG). We thought to analyze TAC density in a full Hounsfield unit (HU) range and to study its association with TAC volume, traditional risk factors, and CVD events. METHODS: Non-enhanced CT images of 1426 patients at intermediate risk were retrospectively reviewed. A calcium density score was estimated as the average of the maximum HU attenuation in all calcified plaques of the entire thoracic aorta (DAV). RESULTS: During a mean 4.0 years follow-up, there were 26 events for a total of 674 patients with TAC > 0. TAC volume and DAV were positively correlated (R = 0.72). The median DAV value was 457 HU (IQ 323-603 HU) and was exponentially related to DAG (R = 0.86). DAV was inversely associated with systolic pressure (p < 0.05), pulse pressure (p < 0.01), hypertension (p < 0.05), and 10-year FRS (p < 0.001) after adjusting for TAC volume. When TAC volume and DAV were included in a logistic model, a significant improvement was shown in CVD risk estimation beyond coronary artery calcium (CAC) (AUC = 0.768 vs 0.814, p < 0.05). In multivariable Cox models, TAC volume and DAV showed an independent association with CVD. CONCLUSIONS: In intermediate risk patients, TAC density was inversely associated with several risk factors after adjustment for TAC volume. A significant improvement was observed over CAC when TAC volume and density were added into the risk prediction model. KEY POINTS: • Calcifications in the aorta can be non-invasively assessed using CT images • A higher calcium score is associated with a higher cardiovascular risk • Measuring the calcifications size and the density separately can improve the risk prediction.

Antitumoral activity of Ficus carica L. on colorectal cancer cell lines.

In traditional medicine, Ficus carica (also known as fig) latex is recognized as a remedy with various therapeutic effects. In the present study we investigated the antitumor activity of Ficus carica extracts and latex. We evaluated the effects of increasing concentrations of Ficus carica extracts and latex on HCT-116 and HT-29 human colorectal cell proliferation using MTT assay and apoptosis induction by evaluating PARP cleavage by Western blot analysis. Peel, pulp, leaves, whole fruit and latex extracts of Ficus carica exerted significant antiproliferative effects on HCT-116 (IC50 values 239, 343, 177, 299, 206 µg/ml) and HT-29 cells (IC50 values 207, 249, 230, 261, 182 µg/ml) after 48h of treatment. Furthermore, treatment with different extracts of Ficus carica induced apoptosis in both HT-29 and HCT-116 cancer cells. Leaves and latex extracts of Ficus carica showed the strongest antiproliferative activities. Overall, our results showed that these natural products are strong apoptosis inducers which suggest their use of for therapeutic purposes.

Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE2 pathways in human M4Beu melanoma cancer cells.

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation of DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE2 pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.

Crataegus azarolus Leaves Induce Antiproliferative Activity, Cell Cycle Arrest, and Apoptosis in Human HT-29 and HCT-116 Colorectal Cancer Cells.

Limited success has been achieved in extending the survival of patients with metastatic colorectal cancer (CRC). There is a strong need for novel agents in the treatment and prevention of CRC. Therefore, in the present study we evaluated the antiproliferative and pro-apoptotic potential of Crataegus azarolus ethyl acetate extract in HCT-116 and HT-29 human colorectal cancer cell lines. Moreover, we attempted to investigate the signaling pathways that should be involved in its cytotoxic effect. The Crataegus azarolus ethyl acetate extract-induced growth inhibitory effect was associated with DNA fragmentation, sub-G1 peak, loss of mitochondrial potential, and poly (ADP-ribose) polymerase (PARP) cleavage. In addition, ethyl acetate extract of Crataegus azarolus induced the cleavage of caspase-8. It has no effect on steady-state levels of total Bcl-2 protein. Whereas Bax levels decreased significantly in a dose-dependent manner in both tested cell lines. Taken together, these findings confirm the involvement of the extrinsic pathway of apoptosis. The apoptotic cell death induced by ethyl acetate extract of Crataegus azarolus was accompanied by an enhancement of the p21 expression but not through p53 activation in human colorectal cancer cells. The above-mentioned data provide insight into the molecular mechanisms of Crataegus azarolus ethyl acetate extract-induced apoptosis in CRC. Therefore, this compound should be a potential anticancer agent for the treatment of CRC.

Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE2 Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells.

Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative 3-hydroxy-3',4,4',5'-tetra-methoxy-chalcone (3-HTMC) on proliferation, cell cycle distribution, apoptosis, and its mechanism of action in human colorectal HT-29 (COX-2 sufficient) and HCT116 (COX-2 deficient) cancer cells. We showed that 3-HTMC decreased cell viability in a dose-dependent manner with a more potent antiproliferative effect on HCT116 than HT-29 cells. Flow cytometric analysis revealed G2 /M cell cycle accumulation in HT-29 cells and significant G2 /M arrest in HCT116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. We demonstrated that 3-HTMC treatment on both cell lines induced apoptotic process associated with overexpression of death receptor DR5, activation of caspase-8 and -3, PARP cleavage, and DNA fragmentation. In addition, 3-HTMC induced activation of PI3K/Akt and MEK/ERK principal survival pathways which delay 3-HTMC-induced apoptosis in both cell lines. Furthermore, COX-2 overexpression in HT-29 cells contributes to apoptosis resistance which explains the difference of sensitivity between HT-29 and HCT116 cells to 3-HTMC treatment. Even if resistance mechanisms to apoptosis reduced chalcone antitumoral potential, our results suggest that 3-HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention. J. Cell. Biochem. 117: 2875-2885, 2016. © 2016 Wiley Periodicals, Inc.

Microparticles, vascular function, and atherothrombosis.

Membrane-shed submicron microparticles (MPs) are released after cell activation or apoptosis. High levels of MPs circulate in the blood of patients with atherothrombotic diseases, where they could serve as a useful biomarker of vascular injury and a potential predictor of cardiovascular mortality and major adverse cardiovascular events. Atherosclerotic lesions also accumulate large numbers of MPs of leukocyte, smooth muscle cell, endothelial, and erythrocyte origin. A large body of evidence supports the role of MPs at different steps of atherosclerosis development, progression, and complications. Circulating MPs impair the atheroprotective function of the vascular endothelium, at least partly, by decreased nitric oxide synthesis. Plaque MPs favor local inflammation by augmenting the expression of adhesion molecule, such as intercellular adhesion molecule -1 at the surface of endothelial cell, and monocyte recruitment within the lesion. In addition, plaque MPs stimulate angiogenesis, a key event in the transition from stable to unstable lesions. MPs also may promote local cell apoptosis, leading to the release and accumulation of new MPs, and thus creating a vicious circle. Furthermore, highly thrombogenic plaque MPs could increase thrombus formation at the time of rupture, together with circulating MPs released in this context by activated platelets and leukocytes. Finally, MPs also could participate in repairing the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization.

Phytochemical potential of Daphne gnidium in inhibiting growth of melanoma cells and enhancing melanogenesis of B16-F0 melanoma.

In this study, we have investigated inhibitory capacity of ethyl acetate, total oligomer flavonoid (TOF), aqueous extracts and beta amyrin acetate, a triterpene isolated from ethyl acetate extract obtained from leaves of Daphne gnidium, on mouse melanoma (B16-F0 and B16-F10 cells) proliferation. Influence of these products on percentage cell distribution in cycle phases and melanogenesis was also studied. Cell viability was determined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and flow cytometry was used to analyse effects of tested compounds on progression through the cell cycle. In addition, amounts of melanin and tyrosinase were measured spectrophotometrically at 475 nm. Ethyl acetate, TOF and aqueous extracts exhibited significant anti-proliferative activity after incubation with the two types of tumour skin cells B16-F0 and B16-F10. Furthermore, cell cycle analysis revealed that cells treated with ethyl acetate and TOF extracts were arrested predominantly in G2-M phase. Ethyl acetate extract has also the ability to enhance melanogenesis and tyrosinase activity of B16-F0 melanoma cells.

[A new strategy for evaluating coronary risk in primary prevention]. / Nouvelle stratégie d'evaluation du haut risque coronaire en prévention primaire.

Prevention of coronary heart disease is a priority for cardiovascular prevention, as coronary deaths account for half of all cardiovascular deaths. About 20% of coronary events occur in high-risk but asymptomatic and apparently healthy subjects. Such patients can be identified by using a novel two-step strategy to evaluate the coronary risk. The first step is obligatory and is based on simple calculation of a multifactorial risk score derived from the Framingham study and integrating all traditional cardiovascular risk factors. The Framingham risk score can be used to estimate the 10-year probability of fatal and non-fatal coronary heart disease and to identify subjects at high coronary risk (probability greater than 20%). The second step is optional and mainly concerns subjects with Framingham scores between 10% and 20% (intermediate risk). A substantial proportion of these subjects are incorrectly classified by the Framingham score and are in fact at high risk. Risk requalification is based mainly on non-invasive imaging of preclinical atherosclerosis in extracranial carotid arteries (ultrasound-assessed plaque) or in coronary arteries (no-contrast CT assessment of coronary calcium). This novel strategy for coronary risk evaluation could help to maintain and improve the ongoing regression of cardiovascular mortality, especially in women and elderly people.

A novel form of melanoma apoptosis resistance: melanogenesis up-regulation in apoptotic B16-F0 cells delays ursolic acid-triggered cell death.

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. The resistance mechanisms are complex and melanoma cells may have diverse possibilities for regulating apoptosis to generate apoptotic deficiencies. In this study, we investigated the relationship between melanogenesis and resistance to apoptosis induced by ursolic acid, a natural chemopreventive agent, in B16-F0 melanoma cells. We demonstrated that cells undergoing apoptosis are able to delay their own death. It appeared that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were clearly implicated in an apoptosis resistance mechanism; while TRP-2, a well known mediator of melanoma resistance to cell death, was repressed. Our results confirm the difficulty of treating melanomas, since, even undergoing apoptosis, cells are nevertheless able to trigger a resistance mechanism to delay death.

Carotid circumferential wall stress homeostasis in early remodeling: theoretical approach and clinical application.

PURPOSE: To assess the influence of cardiovascular risk factors on arterial wall growth and the remodeling process. METHODS: In a theoretical part, we used a well-established relationship linking the rate of thickening of the arterial wall to the circumferential wall stress (CWS) increase. In a clinical part, we measured the intima-media thickness (IMT) in 166 subjects with increased cardiovascular risk score but no treatment for hypertension or hypercholesterolemia, no diabetes, and no cardiovascular disease. Far wall IMT and lumen diameter were measured along the right carotid artery by high-resolution ultrasonography and computerized image analysis. RESULTS: A decreasing linear relationship between IMT and CWS was deduced from the theoretical model, implying that an increase in CWS would result in an IMT increase, and that the higher the IMT-CWS slope, the higher the thickening response. Subjects with advanced age, renal insufficiency, high 10-year Framingham risk, carotid atherosclerosis, and advanced atherosclerosis at other sites had sharper IMT-CWS slope (p < 0.05), in agreement with the homeostasis of CWS hypothesis. CONCLUSIONS: The IMT increase responding to a CWS increase was greater in high-risk patients.

[Distribution of coronary risk in the population]. / Répartition du risque coronarien dans la population.

Of all cardiovascular deaths, those from coronary origin are preponderant. Therefore the reduction of cardiovascular mortality requires improving substantially coronary prevention. Three categories of coronary risk (probability of hard coronary event at 10 years; low <10%, intermediate 10 to 20%, high > 20%) are identifiable via scoring procedure integrating multiple traditional risk factors. Risk is also high, independent of score value, in the case of coexisting major risk factor (diabetes, severe hypertension or hypercholesterolemia) and/or clinically overt coronary, peripheral or cerebral vascular disease. The knowledge of the distribution of coronary risk categories within the population allows defining preventives strategies and estimating needs and costs. Such distribution is pyramidal with the majority of the population at low or intermediate risk while only 15% at high risk. Although largely in minority, the latter convey an important proportion of coronary accidents so justifying the priority given to detection and intensive treatment of high coronary risk condition.

The value of carotid intima-media thickness for predicting cardiovascular risk.

We reviewed prospective epidemiological data in the general population, mostly middle-aged to older persons, to determine the association of carotid intima-media thickness (CIMT) (assessed by B-mode ultrasonography) with cardiovascular risk. Reported risks were expressed as absolute (event risk per persons-years in subjects with a high CIMT) and relative (hazard ratio of high vs low CIMT). They were hardly comparable as the result of differences between the analyzed studies, including the site and procedure of CIMT measurement, the report of adjusted or unadjusted models, and the arbitrary cutoff point to evaluate the CIMTAEs ability to predict risk. Despite these heterogeneities, the following four main conclusions emerged: (1) CIMT was an independent but relatively modest (as judged by absolute risk) predictor of coronary heart disease (CHD); (2) CIMT was an independent predictor for stroke, slightly better than for CHD as judged by the relative risks of both events; (3) CIMT added little to the CHD prediction by risk factors, as judged by c statistic and receiver operating characteristic curve analysis (however, appropriate data for stroke on this important issue were lacking); and (4) the CHD prediction by CIMT was inferior to that by ultrasonography-assessed carotid plaque because plaque may be more representative of atherosclerosis than CIMT.

Chemical composition and biological potential of Thymus Willdenowii Boiss. & Reut. essential oil.

The fresh aerial parts of Thymus willdenowii Boiss. & Reut. (syn. Thymus hirtus Willd.) were hydrodistilled in a Clevenger type apparatus and analyzed by GC and GC-MS. 44 Components were identified representing 97.3%, with 1,8-cineole (34.62%), camphor (18.55%), α-pinene (9.46%) and camphene (5.38%) as the main components. T. willdenowii essential oil was not cytotoxic (CC50 = 97.65 µg/mL) towards Vero non-tumoural cells, exhibiting good antibacterial and antiproliferative (30.8 ± 3.1% inhibition) potentials against four tested pathogenic bacteria and Human colorectal cell line HT-29, respectively. The essential oil did not show a DPPH radical scavenging activity, by Electron Spin Resonance spectroscopy (ESR), and it lacks antiviral effect towards coxsackievirus B3.

Public health implication of solid waste generated by households in Bekwarra Local Government area.

BACKGROUND: This study was conducted in Bekwarra Local Government Area of Cross River State, Nigeria, to determine the public health implication of solid waste generated by households. METHODS: A cross sectional descriptive design was employed, using a semi-structured questionnaire together with an observation checklist to elicit information from the respondents. Proportionate sampling was used to select 400 respondents of 18 years and above for the study area. Data collected were analysed using the Microsoft Excel 2007 and Statistical Package for Social Sciences (SPSS) software version 20. RESULTS: Respondents knowledge concerning solid waste disposal was assessed and the results showed that majority of the respondents 193 (63.7%) had high level of knowledge of solid waste disposal, while 170 (42.5%) had average level of knowledge of solid waste disposal. Wastes produced by households in the study include vegetables (95.5%), ash (94%), clothing/rag (94.2%), wood (95%), and animal waste (86.2%) had the highest abundance. Diseases associated with these wastes produced by households include cholera (18.2%), malaria (47.2%), lassa fever (10.7%) and diarrhea (23.9%) with malaria been the most prevalence infection. CONCLUSION: The result shows solid waste posed a serious health hazard and lead to the spread of infectious diseases. These issues can be addressed through health education and enlightenment of the people on waste disposal.

Endothelial microparticles in diseases.

Microparticles are submicron vesicles shed from plasma membranes in response to cell activation, injury, and/or apoptosis. The measurement of the phospholipid content (mainly phosphatidylserine; PSer) of microparticles and the detection of proteins specific for the cells from which they are derived has allowed their quantification and characterization. Microparticles of various cellular origin (platelets, leukocytes, endothelial cells) are found in the plasma of healthy subjects, and their amount increases under pathological conditions. Endothelial microparticles (EMP) not only constitute an emerging marker of endothelial dysfunction, but are also considered to play a major biological role in inflammation, vascular injury, angiogenesis, and thrombosis. Although the mechanisms leading to their in vivo formation remain obscure, the release of EMP from cultured cells can be caused in vitro by a number of cytokines and apoptotic stimuli. Recent studies indicate that EMP are able to decrease nitric-oxide-dependent vasodilation, increase arterial stiffness, promote inflammation, and initiate thrombosis at their PSer-rich membrane, which highly co-expresses tissue factor. EMP are known to be elevated in acute coronary syndromes, in severe hypertension with end organ damage, and in thrombotic thrombocytopenic purpura, all conditions associated with endothelial injury and pro-thrombotic state. The release of EMP has also been associated with endothelial dysfunction of patients with multiple sclerosis and lupus anticoagulant. More recent studies have focused on the role of low shear stress leading to endothelial cell apoptosis and subsequent EMP release in end-stage renal disease. Improved knowledge of EMP composition, their biological effects, and the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

Effects of extracellular calcium on the growth-differentiation switch in immortalized keratinocyte HaCaT cells compared with normal human keratinocytes.

The keratinocyte growth and differentiation switch, tightly regulated by several mechanisms, is generally associated with decreased proliferation, cell cycle arrest in G0/G1 phase and expression of epidermal differentiation markers, such as keratin 1 (K1), keratin 10 (K10) and involucrin. In vitro, the spontaneously immortalized human keratinocyte cell line HaCaT is often used as a model to study keratinocyte functions. Comparative differentiation studies between HaCaT cells and normal human keratinocytes (NHK) over an extended time-period have rarely been reported. Therefore, we studied their switch from a proliferating to a differentiated state over 13 days. As culture conditions involved changes in cellular responses, cells were cultured in a specific medium for keratinocyte growth and differentiation was induced by increasing extracellular calcium concentration from 0.09 to 1.2 mm. In NHK, addition of calcium-induced morphological changes and concomitant decreased proliferation. For HaCaT cells, calcium addition resulted in morphological changes, but in an unexpected manner, cells were more proliferative than when cultured at low calcium levels. HaCaT cell hyperproliferation correlated with cell cycle analysis, showing an accumulation in S/G2-M phases. Furthermore, RT-PCR and western blot analysis revealed a delay in the expression of the differentiation markers K1, K10 and involucrin in HaCaT cells compared with NHK. In conclusion, even though calcium-induced differentiation was not associated with a decreased cell proliferation, HaCaT cells conserved properties characteristic of differentiation.

Efficacy and safety of coadministration of fenofibrate and ezetimibe compared with each as monotherapy in patients with type IIb dyslipidemia and features of the metabolic syndrome: a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study.

BACKGROUND: Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia. OBJECTIVE: To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal(R)) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01). METHODS: This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C >or=4.13 mmol/L (>or=160 mg/dL), TG >or=1.71 mmol/L and or=150 mg/dL and

Correction of carotid intima-media thickness for adaptive dependence on tensile stress: implication for cardiovascular risk assessment.

PURPOSE: Early artery wall-thickening detected by ultrasound-assessed increased carotid intima-media thickness (IMT) may reflect atherosclerosis or represent an adaptive response to keep homeostasis tensile stress that is related inversely to wall thickness by Laplace's equation. We attempted to discriminate between both mechanisms by correcting IMT for its inverse association with tensile stress. METHODS: Common carotid IMT and lumen diameter (D) where determined in 40 healthy controls and 119 never-treated asymptomatic patients with >or=1 traditional cardiovascular risk factor. The cross-sectional area (CSA) was calculated as pi x IMT x (IMT + D). Tensile stress was approximated by [mean blood pressure x (D/2 x IMT)], and wall shear stress by [(blood viscosity) x 4 x (mean blood velocity/D)]. Inverse regression line relating IMT and tensile stress in controls (p < 0.001) was used as a reference to determine in an individual at-risk patient the IMT deviation, defining DeltaIMT from the regression line of controls at the measured patient's tensile stress. RESULTS: DeltaIMT correlated positively with age (p < 0.05), body mass index (p < 0.05), blood pressure (p < 0.001), and glucose (p < 0.001). In multivariate analysis, DeltaIMT was independently associated with age (p < 0.01), male gender (p < 0.001), and blood pressure (p < 0.001). IMT showed positive association with age (p < 0.001) but not with other risk factors. Also, DeltaIMT, like CSA, correlated positively with tensile stress (p < 0.001) and negatively with wall shear stress (p < 0.05, p < 0.01), whereas IMT correlated negatively with tensile stress (p < 0.001) but not with wall shear stress. CONCLUSION: Correcting IMT for adaptive association with tensile stress may give more strength to carotid evaluation for assessing cardiovascular risk.

Impact of shear stimulus, risk factor burden and early atherosclerosis on the time-course of brachial artery flow-mediated vasodilation.

OBJECTIVES: Our aim was to analyze flow-mediated dilation (FMD) time-course in response to forearm occlusion in the clinical setting. METHODS AND RESULTS: In 50 asymptomatic subjects, monitoring software measuring continuous beat-to-beat change in brachial artery diameter was used to determine FMD magnitude in percentage change in peak diameter from baseline (FMD-DeltaD), time to peak diameter after occlusion release (FMD-t(peak)), integrated FMD response calculated as area under dilation curve (FMD-AUC), maximum FMD rate calculated as maximal slope of dilation (FMD-MDR). FMD-DeltaD and FMD-MDR correlated positively with peak wall shear stress (P < 0.05, P < 0.01). FMD-MDR correlated negatively with age (P < 0.001), Framingham risk score (P < 0.01) and carotid intima-media thickness (P < 0.05), while FMD-DeltaD correlated negatively with Framingham risk score only (P < 0.01). After adjustment, all these correlations were independent of antihypertensive, lipid-lowering and antidiabetic therapies. All but that of FMD-MDR with intima-media thickness were also found in a subgroup of 29 untreated subjects and in a subgroup of 24 untreated and low-risk (FRS < 10%) subjects. FMD-t(peak) and FMD-AUC were not associated with shear stimulus, Framingham risk score, and intima-media thickness. CONCLUSION: The kinetics of dilation (maximum rate) seem more sensitive than their magnitude in assessing FMD performance and its determinants.