Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.

BACKGROUND: The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols. METHODS: We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids). RESULTS: A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age. CONCLUSION: These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81&nbsp;years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Do diabetes and obesity promote hepatic fibrosis in familial heterozygous hypobetalipoproteinemia?

Lette

Cholesterol metabolism in gallstone disease .Preliminary evidence from the analysis of circulating markers of sterol homeostasis

Little is known on the molecular mechanisms underlying cholesterol cholelithiasis even if previous evidence has suggested that reduced production of bile acids might play a role. AIM of the present study was to analyze the hepatic expression of a number of genes involved in bile acid metabolism in human cholelithiasis. METHODS. Surgical liver biopsies were obtained in 11 patients with untreated cholesterol cholelithiasis and 9 gallstone-free subjects; mRNA levels of CYP7A1 and related nuclear receptors and coactivators were assayed by real-time quantitative RT-PCR. RESULTS. No differences were detected the expression of any of the genes studied, with the exception of PPAR-gamma coactivator 1 (PGC-1), a transcriptional coactivator of CYP7A1 involved in insulin sensitivity and energy balance, which was significantly (p &lt; 0.01) less expressed in gallstone subjects. Expression of PGC-1 was linearly correlated with the bile acid receptor FXR in the population of gallstone patients (r = 0.87 on a log scale, p &lt; 0.01). CONCLUSIONS. PGC-1 appears to play a role in the prevention of cholesterol gallstone disease in humans; the finding might suggest a link with insulin resistance conditions. This effect might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models. PGC-1 and related genes might therefore represent molecular targets for the prevention and/or treatment of gallstone disease

Invecchiamento e alterazioni dell\u2019omeosatsi del colesterolo: studio dei livelli plasmatici degli steroli idrossilati come markers metabolici.

Objectives: The modifications of cholesterol metabolism which associate with aging are ill-defined. The objective of this study is to define aging-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analysis of circulating levels of hydroxylated sterols.Methods: We analyzed serum samples from 123 adult subjects (45 male, 78 female, age range 38-78) from the epidemiological M.I.COL. study (Multicentrica Italiana Colelitiasi). The concentrations of the different hydroxysterols, recognized as markers of the main metabolic pathways of cholesterol homeostasis, were determined: synthesis (lathosterol), absorption (campesterol and sitosterol), degradation to bile acids (7alpha-hydroxy-4-cholesten-3-one). Analysis was performed by gas-chromatography - mass spectrometry.Results: a significant correlation was detected between age and cholesterol levels. The lathosterol/cholesterol ratio (an index of cholesterol synthesis) was lower in older (age &gt; 65), compared to younger subjects (102\uf0b139 vs 126\uf0b162 microg/100 microg cholesterol; P &lt; 0.05, t test for independent data). A significant inverse correlation was present between the lathosterol/cholesterol ratio and age. The remaining markers did not show significant modifications with aging, even if a trend toward a reduction of cholesterol markers was present.Conclusions: These data, although preliminary, show a reduction of cholesterol synthesis with aging. The finding might be related with a reduced metabolic need for cholesterol in advancing age, leading to a down-regulation of the main mechanisms of cholesterol uptake in the liver. The possible implications in terms of pharmacological management of hypercholesterolemia remain to be defined

ESTIMATION OF CARDIOVASCULAR RISK IN TYPE 2 DIABETES

Diabetes mellitus is a major risk factor for cardiovascular (CV) events. Many algorithms have been devised to assess CV risk, some of which specific for diabetics. Most of them, however, can hardly be extrapolated to Mediterranean countries. AIM of this study was to analyze CV risk and the incidence of CV events in a local cohort of patients with type 2 diabetes. METHODS. Clinical charts of the Diabetes Clinics of Modena in the period 1991-1995 were analyzed. Patients aged 35-65 with type 2 diabetes and no previous CV disease were eligible. Global CV risk was computed according to Framingham, RISCARD, Progetto Cuore and UKPDS algorithms and compared with the actual rate of CV events over the following 10 years. RESULTS. 2416 patients were screened; 1532 of them (63.4%) were eligible on the basis of predefined criteria and completeness of data. In such population an absolute 10-yr risk rate of 14.6% was observed. When looking at the characteristics of the patients who developed a cardiovascular event compared to those who did not, we found a significant difference in the prevalence of risk factors as systolic blood pressure, age at visit, smoke, duration of diabetic disease and HbA1c. COPD and chronic heart failure also display a higher prevalence in patients with events, suggesting a possible role of these chronic conditions in developing cardiovascular disease. Interestingly, most of the subjects presenting with a CV event had a low to moderate risk estimate at the beginning; this was particularly evident with the Progetto Cuore algorithm. CONCLUSIONS. Estimation of CV risk is largely dependent on the algorithm adopted and on the baseline risk of the reference cohort. Equations designed for a specific population should be adopted. The overall performance of presently available functions is however low. Inclusion of additional risk parameters might hopefully increase the performance of such algorithms, which is presently clearly unsatisfactory. The algorithm derived from the present study will be utilized for a prospective evaluation of CV risk in our local cohort

RISK FOR CARDIOVASCULAR EVENTS IN A LOCAL POPULATION OF DIABETIC PATIENTS.

Diabetes mellitus (DM) is a major risk factor for cardiovascular (CV) events. Many algorithms have been devised to assess CV risk, some of which specific for diabetics. Most of them, however, are based on data which can hardly be extrapolated to Mediterranean countries. AIM of the present study was to analyze CV risk and the incidence of CV events in a local cohort of patients with type 2 DM. METHODS. Clinical charts of two Diabetes Clinics of Modena in the period 1991-1994 were analyzed. Patients aged 35-65 with type 2 DM and no history of CV disease were eligible. Global CV risk was computed according to Framingham, RISCARD, Progetto Cuore and UKPDS algorithms and compared with the actual rate of CV events over the following 10 years. RESULTS. 774 patients were screened; 473 of them (61.1%) were eligible on the basis of predefined criteria and completeness of data. In such population an absolute 10-yr risk rate of 10.8% was observed. When comparing the estimated risk rate according to the different functions, a high degree of variability was present; Italian algorithms were more consistent with the observed data even if only 31% of patients with CV events had a risk > 20% at initial observation. CONCLUSIONS. Estimation of CV risk is largely dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population should be adopted. The overall performance of such functions is however low. The algorithm derived from the present study will be utilized for a prospective evaluation of CV risk in our local cohort

Risk for cardiovascular events in an Italian population of patients with type 2 diabetes

BACKGROUND AND AIM:This study aims to analyse the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: the Framingham study, United Kingdom Prospective Diabetes Study (UKPDS), Riskard study and Progetto Cuore.METHOD AND RESULTS:We analysed clinical charts of the Diabetes Clinics of Modena for the period 1991-95. Patients in the age range of 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. A total of 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-year rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects, we found significant differences in systolic blood pressure, age at visit, smoking, high-density lipoprotein (HDL)-cholesterol, duration of diabetes, glycosylated haemoglobin (HbA1c) and co-morbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore and Riskard show underestimation of events when applied to females.CONCLUSIONS:Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk variables peculiar for diabetes, should be adopted to increase the performance of such functions which is clearly unsatisfactory at present

Correlation between plasma levels of 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic patients

BACKGROUND/AIM: Hepatic bile acid synthesis is the main mechanism whereby the organism can degrade cholesterol. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one have been reported to reflect bile acid synthesis and the expression or activity of the limiting enzyme of the main biosynthetic pathway, cholesterol 7alpha-hydroxylase. Aim of this study was to correlate the levels of this metabolite with the rates of cholesterol 7alpha-hydroxylation in vivo, a direct measurement of bile acid synthesis, in hyperlipidemic patients. DESIGN: Concentrations of 7alpha-hydroxy-4-cholesten-3-one were assayed by gas-liquid chromatography: mass spectrometry in plasma samples obtained in 18 patients with primary hyperlipoproteinemia who previously underwent determination of cholesterol 7alpha-hydroxylation rates in vivo by tritium release analysis. Both determinations were performed in basal conditions and after treatment with hypolipidemic drugs (the fibric acid derivatives gemfibrozil and bezafibrate, cholestyramine alone or associated with simvastatin). RESULTS: Changes in plasma 7alpha-hydroxy-4-cholesten-3-one profile closely reflected in vivo cholesterol 7alpha-hydroxylation rates during treatment with fibrates, cholestyramine and cholestyramine plus simvastatin. When plotting determinations from all studies (n=40), a very strict correlation was disclosed between plasma 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates (r=0.81, P<0.001). CONCLUSIONS: Plasma 7alpha-hydroxy-4-cholesten-3-one closely mirrors measurements of cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic subjects and therefore stands as a reliable marker of global bile acid synthesis. In view of the correlation observed, these data may help to interpret changes of plasma levels of this metabolite in terms of cholesterol balance quantification