Lysosomal Acid Lipase as a Molecular Target of the Very Low Carbohydrate Ketogenic Diet in Morbidly Obese Patients: The Potential Effects on Liver Steatosis and Cardiovascular Risk Factors.

A very low carbohydrate ketogenic diet (VLCKD) is an emerging technique to induce a significant, well-tolerated, and rapid loss of body weight in morbidly obese patients. The low activity of lysosomal acid lipase (LAL) could be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is a common feature in morbidly obese patients. Fifty-two obese patients suitable for a bariatric surgery intervention underwent a 25-day-long VLCKD. The biochemical markers of glucose and lipid metabolism, and flow-mediated dilation (FMD) of the brachial artery were measured before and after VLCKD. LAL activity was measured using the dried blood spot technique in 20 obese patients and in a control group of 20 healthy, normal-weight subjects. After VLCKD, we observed a significant reduction in body mass index, fasting glucose, insulinemia, and lipid profile parameters. No significant variation in FMD was observed. The number of patients with severe liver steatosis significantly decreased. LAL activity significantly increased, although the levels were not significantly different as compared to the control group. In conclusion, VLCKD induces the activity of LAL in morbidly obese subjects and reduces the secretion of all circulating lipoproteins. These effects could be attributed to the peculiar composition of the diet, which is particularly poor in carbohydrates and relatively rich in proteins.

Oxidative balance in lymphocytes from patients with nonalcoholic steatohepatitis.

Oxidative stress is linked to several human diseases, including nonalcoholic steatohepatitis (NASH). In this study, lymphocytes were used as a model to study this disease. These cells offer several advantages for cellular and molecular studies such as easy accessibility, and they are easily accessible and constitute a "time-persistent" system capable of reflecting the condition of the whole organism. Lymphocytes from patients with NASH display oxidative stress features. Among the possible causes for the overproduction of reactive oxygen species in NASH lymphocytes, there might be alterations of enzymatic pathways, auto-oxidation of glucose and mitochondrial superoxide production, which, in turn, would lead to protein oxidative damage. Increased oxidative stress in lymphocytes from patients with NASH may result in a pro-oxidative environment, which, in turn, could modify the pathway of the enzymatic activities. The data confirm that an imbalance between pro-oxidant and antioxidant defense mechanisms may be an important factor in NASH.

Cholesterol metabolism differs after statin therapy according to the type of hyperlipemia.

AIM: Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias. MAIN METHODS: We determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH). KEY FINDINGS: At baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 µmol/mmol cholesterol (p=0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 µmol/mmol cholesterol (p=0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 µmol/mmol cholesterol (p=0.0001), and from 75 to 86 102 µmol/mmol cholesterol, (p=0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol. SIGNIFICANCE: Primary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely "synthesis inhibition" dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.

Cardiovascular risk factors and recommended lipid goals attainment among patients referred in a tertiary care lipid clinic.

BACKGROUND: Many adults are not at recommended lipid levels and the extent of treatment of dyslipidemia remains poor. We investigated the burden of cardiovascular risk and the distance of lipid fractions from the recommended targets by statin therapy and risk status in patients referred to a tertiary care lipid clinic. METHODS: Assessment of cardiovascular risk factors was performed in 1657 patients, mostly dyslipidemics, referred by family physicians to our Lipid Clinic, 393 patients being under statin therapy. The shortfall of lipid fractions from the National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) recommended goals was evaluated. RESULTS: A high prevalence of cardiovascular risk factors was found. LDL cholesterol target was reached by 20% and 45% of untreated and statin treated patients, whereas non-HDL cholesterol target by 13% and 45% of untreated and statin treated patients, respectively. LDL cholesterol was over the goal by 27% in untreated patients and by 25% in statin treated patients. More than 40% and 65% statin treated patients were taking either a low statin dose or statins with low-to-moderate LDL cholesterol lowering efficacy (<30%). A decrease in the proportion of patients at target and greater shortfalls from recommended goals were found from low to high risk categories. CONCLUSION: The shortfall in reaching lipid targets, particularly among high risk statin untreated patients, may be partly explained by delayed or even inadequate lipid lowering therapy. Shortfalls in reaching the targets are not necessarily high and might be possibly managed at a primary care level.

Preclinical vascular damage in white postmenopausal women: the relevance of osteoprotegerin.

Osteoprotegerin (OPG) has recently been implicated in human atherogenesis. Abdominal obesity represents an established risk factor for the onset and development of atherosclerotic damage. The aim of the present study was to investigate the link between OPG and abdominal fat and the relationship to precocious features of atherosclerotic disease such as brachial flow-mediated vasodilation (FMV) and the intima-media thickening (IMT) in 195 white postmenopausal women (age range, 43-75 years). The study population was divided into 2 groups: group 1-waist circumference <80 cm and group 2-waist circumference > or = 80 cm. Group 2 had higher menopausal years, body mass index, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, and carotid IMT. High-density lipoprotein cholesterol was higher in group 1. Afterward, these groups were divided on the basis of a cutoff value of OPG (6.85 pmol/L) that was the median of its distribution: patients with OPG < or = 6.85 pmol/L were OPG(-), and those with OPG >6.85 pmol/L were OPG(+). The OPG(+) subjects in both had lower brachial FMV and higher carotid IMT in comparison with OPG(-) subjects. At the multivariate regression analysis, waist circumference, high-density lipoprotein cholesterol, C-reactive protein, and OPG were predictors of carotid mean IMT (beta = 0.55, P = .001; beta = -0.14, P = .001; beta = 0.16, P = .001; and beta = 0.14, P = .05, respectively) and age, OPG, low-density lipoprotein cholesterol, and brachial diameter of brachial FMV (beta = -0.13, P = .05; beta = -0.25, P = .001; beta = -0.14, P = .024; and beta = 0.48, P = .001, respectively). The conclusions are as follows: first, OPG levels did not appear to be conditioned by a risk factor such as abdominal obesity; and second, OPG levels are mainly linked to the evidence of vascular damage. On this basis, we could speculate that OPG levels may be considered not a cardiovascular risk condition but a defense against atherosclerotic progression.

Human endothelial impairment in sepsis.

The onset of sepsis is often non-specific, and its severity is cryptic. The pathophysiological mechanism of sepsis development involves vascular alteration and, in particular, the impairment of endothelial function. Aim of the study was to evaluate the potential implications of brachial endothelial function assessment in patients affected by Gram-negative sepsis. Forty-five young patients (mean age 41+/-8 years, 18 males) with Gram-negative sepsis were included; at admission time (T0) signs and symptoms, clinical and laboratory data were collected; the Sequential Organ Failure Assessment (SOFA) score was assessed at the time of the access along with the evaluation of brachial flow-mediated vasodilation (FMV). The same parameters were repeated 3 days after hospitalization (T1). Study population at the hospitalization time was divided on the basis of a brachial FMV cut off: at the T0 subjects with FMV<7.5% had lower white blood cell count in comparison to subjects with FMV> or =7.5% (6693+/-1559 mmc versus 14,270+/-2399 mmc); subjects with FMV<7.5% had a significant increase in SOFA score at T1 (4+/-1 versus 6+/-1) and a significant reduction of brachial FMV at T1 (4.8+/-2.7% versus 3.7+/-2.6%) (all p<0.05). FMV at the admission time was predicted by white blood cells (beta=0.65; p<0.001) and brachial diameter (beta=-0.292; p<0.05); Delta changes in FMV were predicted by changes in SOFA score (beta=-0.41; p<0.05). In conclusion, the present study indicates that in the initial phase of sepsis an impairment of brachial FMV anticipated the progression in organ failures; these considerations support the potential utility of brachial FMV in clinical practice in acute pathologies as septic state.

Is estimated cardiovascular risk higher in HIV-infected patients than in the general population?

Cardiovascular disease (CVD) is an increasing concern for human immunodeficiency virus (HIV)-infected patients, and risk assessment is recommended in routine HIV care. The absolute cardiovascular risk in an individual is determined by several factors, and various algorithms may be applied. To date, few comparisons of HIV patients with persons of the same age from the general population have been conducted. We hypothesized that the calculated risk of CVD may be increased in HIV patients. The probability for acute coronary events within 10 y (Framingham Risk Score) and the probability for fatal cardiovascular disease (SCORE algorithm) were assessed in 403 consecutive HIV-positive subjects free from overt cardiovascular disease, as well as in 96 age- and gender-matched control subjects drawn from the general population living in the same geographical area. The average 10-y risk for acute coronary events (Framingham Risk Score) was 7.0%+/-5% in HIV subjects and 6.3%+/-5% in the control group (p =0.32). The 10-y estimated risk for cardiovascular mortality (SCORE algorithm) was 1.23%+/-2.3% and 0.83%+/-0.9%, respectively (p =0.01). The main contributor to the increased CVD risk was the high proportion of smokers, but not an increase in cholesterol level. In conclusion, a limited increase in estimated risk of CVD was found in HIV-infected patients compared to the general population. In HIV-infected individuals other factors of less value in the general population and not included in any cardiovascular algorithm might be important. In our patients intervention to modify traditional risk factors should be addressed primarily towards modifying smoking habits.

Racial difference in endothelial function: role of the infective burden.

There is much evidence to suggest the existence of racial differences between blacks and whites in the behaviour of endothelial function. Infective state, sustained by viral or bacterial agents, may injure the endothelial surface favouring the onset and progression of atherosclerotic process, mainly by an inflammatory mechanism. The aim of the study was to investigate endothelial function, expressed as brachial flow-mediated vasodilation (FMV), in black and white healthy subjects, along with antibody titer to cytomegalovirus, hepatitis virus (B, C), herpes virus-1 and 2, Epstein-Barr, Chlamydia pneumoniae and the expression of adhesion molecules. We enrolled 22 young (mean age 27+/-8 years) healthy subjects of black race (10 males) and 20 healthy young subjects (10 males, mean age 28+/-9 years) of white race. Total infectious burden (TIB) was defined as the number of serological positive infections. Black subjects have a reduced brachial FMV (6.9+/-3.5% versus 11.6+/-3.0%, p<0.01) and increased values of hsCRP (0.35+/-0.15 mg/dL versus 0.07+/-0.08 mg/dL, p<0.05), white cells (8578+/-1041/mmc versus 5833+/-998/mmc, p<0.01) and adhesion molecules (respectively: sVCAM-1 945+/-142 versus 779+/-93, sICAM-1 534+/-107 ng/mL versus 325+/-80 ng/mL; both p<0.01) in comparison to white subjects. The total infectious burden in black race was significantly higher than in white race (5+/-1 versus 2+/-1, p<0.01). At the univariate analysis, brachial FMV was significantly related to the levels of adhesion molecules (respectively: sVCAM-1 r=-0.49; sICAM-1 r=-0.50, both p<0.05), hsCRP (r=-0.47, p<0.05) and white blood cells (r=-0.43, p<0.05). TIB was associated with brachial FMV (r=-0.64, p<0.05), sVCAM-1 (r=0.55, p<0.05) and hsCRP (r=0.47, p<0.05). At the multivariate analysis the only predictive variables for brachial FMV were hsCRP, TIB and brachial diameter (respectively: beta=-0.49, -0.19, -0.54, all p<0.05). This study confirms that endothelial reactivity is impaired in young African black patients; moreover its behavior is strictly related to the inflammatory state and to the total infectious burden.

Artichoke juice improves endothelial function in hyperlipemia.

Artichoke extracts have been shown to produce various pharmacological effects, such as the inhibition of cholesterol biosynthesis and of LDL oxidation. Endothelial dysfunction represents the first stage of atherosclerotic disease; it is usually evaluated in humans by a noninvasive ultrasound method as brachial flow-mediated vasodilation (FMV) and by the determination of several humoral markers such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. Aim of the study was to investigate the effects of dietary supplementation with artichoke juice on brachial FMV of hyperlipemics. We studied 18 moderately hyperlipemic patients (LDL cholesterol > 130 <200 mg/dl and/or triglycerides >150 <250 mg/dl) of both genders and 10 hyperlipemic patients, matched for age, sex and lipid parameters. All subjects were under isocaloric hypolipidic diet. A basal determination of serum lipids, soluble VCAM-1, ICAM-1, E-selectin and brachial FMV was performed. Thereafter patients were given 20 ml/die of frozen artichoke juice. The same parameters were repeated after 6 weeks. After artichoke treatment there was an increase of triglycerides (156 +/- 54 vs 165 +/- 76 mg/dL, p <0.05) and a reduction of total cholesterol (261 +/- 37 vs 244 +/- 38 mg/dL, p <0.05) and LDL cholesterol (174 +/- 31 vs 160 +/- 34 mg/dL, p <0.05). Controls showed a significant decrease in total and LDL cholesterol (respectively: 267 +/- 22 vs 249 +/- 20 mg/dL and 180 +/- 24 vs 164 +/- 23 mg/dL, both p <0.001). After artichoke there was a decrease in VCAM-1(1633 +/- 1293 vs 1139 +/- 883 ng/mL, p <0.05) and ICAM-1(477 +/- 123 vs 397 +/- 102 ng/mL, p <0.05), brachial FMV increased (3.3 +/- 2.7 vs 4.5 +/- 2.4%, p <0.01), while controls did not exhibit significant changes in VCAM-1, ICAM-1, E-selectin and brachial FMV. Univariate analysis showed that, in artichoke patients, changes of VCAM-1 and ICAM-1 were significantly related to changes in brachial FMV (respectively: r=-0.66 and r=-0.62; both p <0.05). In conclusion, artichoke dietary supplementation seems to positively modulate endothelial function in hypercholesterolemia.

Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women.

Statins are able to reduce cardiovascular morbility and mortality mainly through their hypocholesterolemic effect. Beyond the inhibition of cholesterol synthesis, the identification of "ancillary" mechanisms has motivated studies evaluating the relationship between the use of statins and the modification of bone mineral density (BMD). To date, clinical trials have provided discordant results. The aim of our study was to evaluate whether simvastatin treatment (40 mg/d) could modify BMD in hypercholesterolemic women (n = 40) after a 2-year treatment as compared with a control group treated only with diet (n = 20) and matched by gender, age, body mass index (BMI), lipids, menopausal age, and BMD and the number of osteopenic, osteoporotic, and normal women (on the basis of T-score value). Exclusion criteria were secondary hyperlipemias and osteoporosis and current or previous therapy with statins, bisphosphonates, and estrogens. The BMD was measured at the lumbar spine and hip by dual energy x-ray absorpiometry (DEXA). In the group treated by simvastatin, BMD, both on the spine and femoral hip, showed a significant increase after 8 and 24 months, respectively (0.878 +/- 0.133 v 0.893 +/- 0.130 and 0.907 +/- 0.132; 0.840 +/- 0.101 v 0.854 +/- 0.101; and 0.863 +/- 0.10, P <.001); there was a percentage increase of 1.7% after 8 months and 3.3% after 24 months at the spine; at the femoral hip, BMD increased 1.6% after 8 months and 2.7% after 24 months. The group treated only with hypolipidic diet demonstrated after 8 and 24 months a slight decrease in BMD both on the spine and femoral hip (respectively, 0.884 +/- 0.175 v 0.872 +/- 0.174 and 0.861 +/- 0.164; 0.860 +/- 0.110 v 0.853 +/- 0.096 and 0.847 +/- 0.095; P <.05). In conclusion, as partly suggested by retrospective or observational data, this longitudinal study indicates that simvastatin treatment exerts a beneficial effect on BMD.

Plasma C-reactive protein in subjects with hypo/hyperalphalipoproteinemias.

Hypoalphalipoproteinemia (Hypo-A), a lipid disorder characterized by low high-density lipoprotein (HDL)-cholesterol (HDL-C) levels, is frequently associated with an increased risk of suffering future coronary heart disease (CHD). Conversely, hyperalphalipoproteinemia (Hyper-A) is a characterized by high HDL-C concentrations and is possibly associated with longevity and protection against CHD. Whether plasma C-reactive protein (CRP) level, an emerging marker of CHD risk, may be influenced by either extremely low or high HDL-C concentrations is yet to be determined. Plasma levels of lipids and CRP have been measured in 52 middle-aged men and women, clinically free of CHD, including 20 subjects with Hypo-A, 12 with Hyper-A, and 20 healthy normolipemic age-matched controls. CRP levels were the highest in Hypo-A [0.22 mg/dL (interquartile range, 0.15 to 0.44)], the lowest in Hyper-A [0.03 mg/dL (0.02 to 0.07)], and intermediate in the control group [0.10 mg/dL (0.05 to 0.20)]. Differences in plasma CRP concentrations were significant between Hypo-A and the other 2 groups, as well as between Hyper-A and controls. Plasma CRP levels showed a particularly strong correlation with plasma HDL-C concentrations (r = -.66, P <.001). In multivariate models, HDL-C represented the only significant predictor of circulating levels of CRP. In conclusion, in subjects with Hypo-A or Hyper-A, HDL-C levels may account for plasma CRP variations independent of other potential cardiovascular risk factors.

Early vascular damage in primary hypoalphalipoproteinemia.

The relationship between hypoalphalipoproteinemia (hypoalpha), a metabolic disorder characterized by reduced high-density lipoprotein (HDL) cholesterol levels, and atherosclerotic disease is not completely understood. We investigated arterial functional and structural changes in 19 subjects with hypoalpha (HDL cholesterol < or = 0.7 mmol/L for men and < or = 0.8 mmol/L for women; 13 men; 47 +/- 7 years) and in 21 healthy control subjects (11 men; 46 +/- 13 years). Brachial-artery flow-mediated vasodilation (FMV) and intima-media thickness (IMT) of the carotid and femoral arteries were determined in all subjects. FMV was significantly lower in hypoalpha than in controls (5.6% +/- 4.3% v 8.2% +/- 2.7%; P <.05). IMT was greater in hypoalpha than in controls at both the internal carotid (0.83 +/- 0.1 mm v 0.69 +/- 0.1 mm) and superficial femoral level (0.83 +/- 0.2 mm v 0.68 +/- 0.1 mm; both P <.05). FMV had a positive correlation with HDL cholesterol (r =.42, P =.06) and a negative one with triglycerides (r = -0.38, P =.01). An inverse relationship was found between HDL cholesterol and internal carotid and superficial femoral IMT (r = -0.64 and r = -0.60, respectively; P <.01 for both) and a positive one between triglycerides and internal carotid and superficial femoral IMT (r =.53 and r =.47, P <.05). In a multivariate regression analysis, brachial FMV was predicted by HDL cholesterol and brachial diameter (beta =.42 and -0.43, respectively; both P <.05). HDL cholesterol was the only significant predictor of internal carotid and superficial femoral IMT (beta = -0.45 and -0.49, respectively; both P <.05). In conclusion, subjects with primary hypoalpha, without overt cardiovascular disease, are characterized by an impaired endothelial function and by an increase in large-artery IMT.