Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Uric acid and bone mineral density in postmenopausal osteoporotic women: the link lies within the fat.

The association between serum uric acid (SUA) levels and bone mineral density (BMD) is controversial. Fat accumulation is linked to SUA and BMD, thus possibly explaining the mixed results. We found that adiposity drives part of the association between SUA and BMD in women with postmenopausal osteoporosis. INTRODUCTION: Both positive and negative associations between SUA and BMD have been reported. SUA levels and BMD increase with higher body weight and other indices of adiposity; hence, the association between SUA and BMD might be a consequence of the confounding effect of adiposity. We investigated in this cross-sectional study whether the association between SUA and BMD is independent of measures of fat accumulation and other potential confounders. METHODS: SUA levels, femur BMD, markers of bone metabolism, body mass index (BMI), fat mass (FM), waist circumference (WC), and abdominal visceral fat area were measured in 180 treatment-naive postmenopausal osteoporotic women (mean age 66.3 ± 8.5 years, age range 48-81 years). RESULTS: Women with higher SUA levels (third tertile) had significantly higher femur BMD and lower cross-linked C-terminal telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels. SUA levels were positively associated with all indices of adiposity. In multivariable analysis with femur BMD as dependent variable, the association between logarithmic (LG)-transformed SUA levels and BMD (beta = 0.42, p < 0.001) was lessened progressively by the different indices of adiposity, like LG-BMI (beta = 0.22, p = 0.007), LG-WC (beta = 0.21, p = 0.01), LG-FM (beta = 0.18, p = 0.01), and LG-abdominal visceral fat area (beta = 0.12, p = 0.05). The association between SUA levels and markers of bone metabolism was dependent on the effect of confounders. CONCLUSION: In postmenopausal osteoporotic women, the strong univariable association between SUA levels and femur BMD is partly explained by the confounding effect of indices of adiposity.

Increased Bone Resorption: A Possible Pathophysiological Link Between Hypovitaminosis D and Peripheral Arterial Disease.

OBJECTIVE/BACKGROUND: Vitamin D deficiency has been associated with the prevalence and severity of peripheral arterial disease (PAD); nevertheless, data on bone turnover in patients with PAD is lacking. The present study investigates a possible relationship between the markers of bone turnover and the presence and severity of PAD. METHODS: The study examined 143 patients, with a mean ± SD age of 75.3 ± 8.5 years (range 50.0-93.0 years), of both sexes, admitted to a department of internal medicine. All patients underwent ankle brachial index (ABI) assessment by Doppler velocimetry. Serum levels of 25(OH) vitamin D and two markers of bone turnover, C-terminal telopeptide of type I collagen (sCTX) and bone isoenzyme of alkaline phosphatase, were measured. The differences between patients with normal ABI and patients with PAD were analyzed. Pearson and Spearman correlation coefficients were calculated and independent predictors were identified through a stepwise linear regression analysis. Odds ratios were calculated with a logistic regression model. RESULTS: Compared with patients with a normal ABI (≥0.90), patients with PAD (ABI < 0.90) presented with significantly lower levels of 25(OH) vitamin D (12.2 ± 9.6 ng/mL vs. 16.7 ± 8.7 ng/mL; p = .006) and a significantly higher concentration of sCTX (1.1 ± 0.7 ng/mL vs. 0.6 ± 0.4 ng/mL; p < .001). There was a positive correlation between ABI and serum concentration of 25 (OH) vitamin D (r = 0.3; p < .001), whereas ABI was inversely correlated with the concentration of sCTX (r = -0.358; p < .001). At logistic regression analysis, age, cigarette smoking, and both vitamin D and sCTX were independent predictors of an ABI < 0.90. CONCLUSION: These results support the hypothesis that hypovitaminosis D and increased bone turnover are risk factors for the presence and severity of PAD. Furthermore, the presence of PAD, even if asymptomatic and diagnosed by a reduced ABI, could identify a population at risk for osteoporosis and osteomalacia.

Association between circulating osteoblast progenitor cells and aortic calcifications in women with postmenopausal osteoporosis.

BACKGROUND AND AIMS: Ectopic artery calcification has been documented in women with postmenopausal osteoporosis, in whom an imbalance in the number of circulating osteoprogenitor cells (OPCs) has been identified. Circulating OPCs form calcified nodules in vitro; however, it remains unknown whether an association exists between the number of circulating OPCs and aortic calcifications. We investigated the relationship between OPCs and aortic calcifications in women with postmenopausal osteoporosis. METHODS AND RESULTS: The number of circulating OPCs was quantified by FACS analysis in 50 osteoporotic postmenopausal women. OPCs were defined as CD15-/alkaline-phosphatase(AP)+ cells coexpressing or not CD34. Participants underwent measurement of markers of bone metabolism, bone mineral density and abdominal aortic calcium (AAC) by 64-slice computed tomography. Patients with AAC were older, had lower 25(OH)vitamin D levels and higher circulating CD15-/AP+/CD34- cells than those without AAC. Significant correlates of AAC included age (rho = 0.38 p = 0.006), calcium (rho = 0.35 p = 0.01), 25(OH)vitamin D (rho = -0.31, p = 0.03) and the number of CD15-/AP+/CD34- cells (rho = 0.55 p < 0.001). In regression analyses, the log-transformed number of CD15-/AP+/CD34- cells was associated with the presence (OR = 6.45, 95% CI 1.03-40.1, p = 0.04) and severity (ß = 0.43, p < 0.001) of AAC, independent of age, 25(OH)vitamin D, calcium and other potential confounders. Patients with low 25(OH)vitamin D and high CD15-/AP+/CD34- cells had higher median AAC than other patients (1927/µL, 862-2714/µL vs 147/µL, 0-1665/µL, p = 0.003). CONCLUSION: In women with postmenopausal osteoporosis, the number of circulating CD15-/AP+/CD34- cells is significantly associated with increased aortic calcifications, that appear to be correlated also with reduced 25(OH)vitamin D levels.

Imbalance between endothelial injury and repair in patients with polymyalgia rheumatica: improvement with corticosteroid treatment.

OBJECTIVES: Polymyalgia rheumatica (PMR) is a rheumatic disease that is characterized by intense activation of systemic inflammation. Systemic inflammation has been associated with an imbalance between endothelial injury and repair, defined by an increased number of circulating endothelial microparticles (EMPs) and a reduced number of endothelial progenitor cells (EPCs). We investigated the association between inflammation and endothelial injury and repair in patients with PMR and evaluated the effects of corticosteroid therapy on EMP and EPC levels. DESIGN, SETTING AND SUBJECTS: We conducted a case-control study in 34 patients with never-treated active PMR and 34 healthy age- and sex-matched controls. Patients with PMR participated in a 1-month intervention open-label study with corticosteroid therapy. Circulating EMPs (CD31+/CD42-) and EPCs (CD34+/KDR+) were quantified by fluorescence-activated cell sorting analysis. RESULTS: Patients with PMR had an increased EMP/EPC ratio compared with controls [median (IQR): 6.5 (3.0-11.5) vs. 1.1 (0.7-1.5), P < 0.001], because of both increased EMP and reduced EPC levels. Levels of C-reactive protein (CRP) were associated with an increased EMP/EPC ratio (ß = 0.48, P = 0.001), irrespective of traditional cardiovascular risk factors. Corticosteroid therapy led to a significant CRP reduction [from 3.9 (1.5-6.7) to 0.6 (0.2-1.2) mg dL(-1) , P < 0.05], paralleled by a consistent 81% decline in the EMP/EPC ratio. CRP and EMP/EPC ratio reductions were significantly correlated (rho = 0.37, P = 0.04). CONCLUSIONS: Polymyalgia rheumatica is associated with a significant imbalance between endothelial injury and repair, which is dependent on the degree of systemic inflammation. Attenuation of inflammation by short-term corticosteroid therapy might have a role in limiting endothelial fragmentation and promote endothelial repair.

Non-cholesterol sterols in different forms of primary hyperlipemias.

BACKGROUND AND AIMS: We investigated the behaviour of non-cholesterol sterols, surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol), in primary hyperlipemias. METHODS AND RESULTS: We studied 53 patients with polygenic hypercholesterolemia (PH), 38 patients with familial combined hyperlipemia (FCH), and 19 age- and sex-matched healthy control subjects. In all participants, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled to mass spectrometry. To correct for the effect of plasma lipid levels, non-cholesterol sterol concentrations were adjusted for plasma cholesterol (10² µmol/mmol cholesterol). Patients with FCH were more frequently men, and had higher body mass index (BMI), fasting glucose, insulin and HOMA-IR. Lathosterol was higher in FCH than in pH or controls (p < 0.05). Campesterol was significantly lower in FCH (p < 0.05), while no differences were found between pH and controls. Sitosterol displayed higher values in pH compared to FCH (p < 0.001) and controls (p < 0.05). Spearman's rank correlations showed positive correlations of lathosterol with BMI, waist circumference, HOMA-IR, triglycerides, apoprotein B, and a negative one with HDL-cholesterol. Sitosterol had a negative correlation with BMI, waist circumference, HOMA-IR, triglycerides, and a positive one with HDL-cholesterol and apoprotein AI. Multivariate regression analyses showed that cholesterol absorption markers predicted higher HDL-cholesterol levels, while HOMA-IR was a negative predictor of sitosterol and BMI a positive predictor of lathosterol. CONCLUSIONS: Our findings suggest the occurrence of an increased cholesterol synthesis in FCH, and an increased cholesterol absorption in pH. Markers of cholesterol synthesis cluster with clinical and laboratory markers of obesity and insulin resistance.

Patterns of cholesterol metabolism: pathophysiological and therapeutic implications for dyslipidemias and the metabolic syndrome.

Investigating cholesterol metabolism, which derives from balancing cholesterol synthesis and absorption, opens new perspectives in the pathogenesis of dyslipidemias and the metabolic syndrome (MS). Cholesterol metabolism is studied by measuring plasma levels of campesterol, sitosterol and cholestanol, that is, plant sterols which are recognised as surrogate cholesterol-absorption markers and lathosterol or squalene, that is, cholesterol precursors, which are considered surrogate cholesterol-synthesis markers. This article presents current knowledge on cholesterol synthesis and absorption, as evaluated by means of cholesterol precursors and plant sterols, and discusses patterns of cholesterol balance in the main forms of primary hyperlipidaemia and MS. Understanding the mechanism(s) underlying these patterns of cholesterol synthesis and absorption will help to predict the response to hypolipidemic treatment, which can then be tailored to ensure the maximum clinical benefit for patients.

Circulating immature osteoprogenitor cells and arterial stiffening in postmenopausal osteoporosis.

BACKGROUND AND AIMS: An increased number of circulating osteoprogenitor cells (OPCs) expressing bone-related proteins and the stem cell marker CD34 have been identified in women with postmenopausal osteoporosis, who also have stiffer arteries than nonosteoporotic subjects. We investigated whether an increased number of circulating OPCs underlies the association of osteoporosis with arterial stiffness. METHODS AND RESULTS: The number of circulating OPCs was quantified by FACS analysis in 120 postmenopausal women with or without osteoporosis. OPCs were defined as CD34+/alkaline phosphatase(AP)+ or CD34+/osteocalcin(OCN)+ cells. Participants underwent cardiovascular risk factor assessment, measurement of bone mineral density (BMD), and aortic pulse wave velocity (aPWV) as a measure of arterial stiffness. Osteoporotic women had higher aPWV (9.8 ± 2.8 vs 8.5 ± 1.9 m/s, p = 0.005) and levels of CD34+/AP+ and CD34+/OCN+ cells than nonosteoporotic controls [1045 n/mL (487-2300) vs 510 n/mL (202-940), p < 0.001; 2415 n/mL (1225-8090) vs 1395 n/mL (207-2220), p < 0.001]. aPWV was associated with log-CD34+/AP+ (r = 0.27, p = 0.003), log-CD34+/OCN+ cells (r = 0.38, p < 0.001). In stepwise regression analysis CD34+/OCN+ cells, age, systolic blood pressure and heart rate were significant predictors of aPWV (Model R = 0.62, p < 0.001), independent of cardiovascular risk factors, parathyroid hormone levels and osteoporotic status. CONCLUSION: In women with postmenopausal osteoporosis an increased availability of circulating osteoprogenitor cells has a detrimental influence on arterial compliance, which may in part explain the association between osteoporosis and arterial stiffening.

Association between circulating osteoprogenitor cell numbers and bone mineral density in postmenopausal osteoporosis.

UNLABELLED: The role of circulating osteoprogenitor cells in postmenopausal osteoporosis is unknown. We found that alkaline-phosphatase-positive (AP+) cells are the lacking cells in osteoporosis, whose reduction is related to bone loss. Conversely, the increased number of alkaline phosphatase/CD34-positive cells may reflect the reactive bone marrow contribution to bone formation. INTRODUCTION: Circulating osteoprogenitor cells mineralize in vitro and in vivo. Loss of osteogenic cells may account for bone loss in osteoporosis. We studied whether there is an association between the number of circulating osteoprogenitor cells and bone mineral density (BMD) in postmenopausal women with and without osteoporosis. METHODS: The number of circulating AP+, osteocalcin-positive (OCN+), AP+/CD34+, and OCN+/CD34+ cells was quantified in 54 postmenopausal osteoporotic women and 36 age-matched nonosteoporotic controls. RESULTS: The number of AP+ cells was lower in osteoporotic women than in controls (127 +/- 16 vs 234 +/- 23 per microliter; p < 0.001); higher levels of AP+/CD34+, OCN+, and OCN+/CD34+ cells were found in osteoporotic than controls (p < 0.01 for all). The number of AP+ cells was correlated with lumbar BMD (rho = 0.29; p = 0.008) and proximal femur BMD (rho = 0.31; p = 0.005) whereas inverse correlations were found between AP+/CD34+ cells, OCN+, OCN+/CD34+, and BMD. Reduced AP+ cells and increased AP+/CD34 +, OCN+, and OCN+/CD34+ cells were predictors of low BMD, independent of traditional risk factors for osteoporosis. CONCLUSION: In postmenopausal osteoporotic women, a reduced number of circulating AP+ cells and increased levels of AP+/CD34+, OCN+, and OCN+/CD34+ cells are associated with reduced bone mineral density, the interpretation of such a cellular imbalance needing exploration.

Lifestyle intervention improves microvascular reactivity and increases serum adiponectin in overweight hypertensive patients.

BACKGROUND AND AIMS: Obesity and hypoadiponectinemia are often associated with high blood pressure. Moreover, microvascular dysfunction is reported to be an early event in patients with hypertension and may be involved in the pathogenesis of organ damage. METHODS AND RESULTS: We investigated the impact of 8-week moderate-intensity aerobic training on adiponectin plasma levels and skin microvascular reactivity in 24 overweight sedentary patients (18 men, age 44+/-6 years, body mass index 28+/-3 kg/m(2)) with never-treated grade 1 essential hypertension. Twenty-four age- and sex-matched hypertensive patients, who were examined twice at 8-week intervals in the absence of exercise training, served as controls. Exercise training was followed by a significant reduction in waist circumference (from 97+/-9 to 95+/-9 cm, p<0.05) and an increase in adiponectin plasma levels (from 11.9+/-3 to 12.5+/-4 mg/L, p<0.05). An inverse correlation was found between adiponectin change and waist circumference change (r=-0.43, p<0.05). The area under the curve after post-occlusive reactive hyperemia at skin laser-Doppler examination increased significantly after aerobic training (from 876+/-539 to 1468+/-925 PU/s, p<0.001). A positive correlation was found between exercise-induced variations of post-occlusive reactive hyperemia and adiponectin plasma levels (r=0.41, p<0.05). Office or 24-h blood pressure values did not change significantly. CONCLUSION: In sedentary overweight patients with mild hypertension, moderate aerobic training improves cutaneous microvascular reactivity and adiponectin plasma levels. These changes precede blood pressure reduction and may serve as biomarkers of the efficacy of non-drug treatment in hypertensive patients.

Case report. Hyperlipoproteinaemia(a): which is the optimal therapy? A case report.

This case report presents the clinical history of a patient with elevated lipoprotein(a) and small size isoform, associated with mixed hyperlipaemia, which was probably familial combined hyperlipaemia. After premature myocardial infarction, the subject was treated with fibrates. Niacin was started after recurrence. One year ago, after another episode of acute coronary syndrome, rosuvastatin was added to niacin. The atherogenicity of this lipid disorder, along with the different options for therapy is discussed.

Endothelial progenitor cells are mobilized after major laparotomic surgery in patients with cancer.

The progression of cancer is largely dependent on neoangiogenesis. Circulating endothelial progenitor cells (EPC) have the ability to form complete vascular structures in vitro and play a crucial role in tumor vasculogenesis. Emerging evidence suggests that surgical injury may induce the mobilization of EPC in animal models, and this might have a negative effect on the prognosis of cancer patients. We studied 20 patients (10 men, 65+/-13 years) undergoing laparotomy for surgical treatment of various forms of abdominal cancer, and 20 age- and sex-matched healthy control subjects. The number of circulating EPC, defined as CD34+/KDR+ cells identified among mononuclear cells isolated from peripheral venous blood, was determined preoperatively and at days 1 and 2 after surgery. Surgery induced a significant increase in circulating EPC levels at day 1 (from 278/mL, interquartile range 171-334, to 558/mL, interquartile range 423-841, p<0.001) and day 2 (709/mL, interquartile range 355-834, p<0.001)compared with baseline values. EPC levels did not change in control subjects. Seven subjects who underwent laparotomic surgery for non-neoplastic disease also showed an increase in EPC levels after surgery (p=0.009 and p=0.028 at day 1 and day 2, respectively). We conclude that patients undergoing elective laparotomic surgery for cancer demonstrate an increase in EPC post-operatively. The potential adverse effects of surgical stress-induced EPC mobilization on tumor and metastasis growth in cancer patients need to be addressed in future studies.

Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: a multicenter Italian study.

BACKGROUND AND AIMS: Plant sterols, added to several food sources, lower serum cholesterol concentrations. Plant sterol-induced cholesterol lowering is paralleled by a mild decrease in plasma levels of the antioxidant beta-carotene, the amount of this decrease being considered clinically non-significant. Whether the effect on lipid profile of daily consumption of plant sterol-enriched low-fat fermented milk (FM) is paralleled by a concomitant variation in a reliable marker of the oxidative burden like plasma isoprostane levels is unresolved. METHODS AND RESULTS: The effect of plant sterol consumption on plasma lipid and isoprostane levels of hypercholesterolemic patients was evaluated in a multicenter, randomized double blind study. Hypercholesterolemic patients consumed a FM daily for 6 weeks. Subjects were randomized to receive either 1.6g of plant sterol-enriched FM (n=60) or control FM product (n=56). After 6 weeks of plant sterol-enriched FM consumption, LDL cholesterol was reduced from 166.2+/-2.0 to 147.4+/-2.8 mg/dL (p=0.01). A significant reduction was observed for total cholesterol (from 263.5+/-2.6 to 231.0+/-3.2mg/dL, p=0.01). There was greater LDL cholesterol lowering among hypercholesterolemic patients with higher LDL cholesterol at baseline. We found a reduction of plasma 8-isoprostane in patients taking plant sterol-enriched FM (from 43.07+/-1.78 to 38.04+/-1.14 pg/ml, p=0.018) but not in patients taking the control product (from 42.56+/-2.12 to 43.19+/-2.0 pg/ml, p=NS). Campesterol and beta-sitosterol levels were not influenced by phytosterol consumption. CONCLUSIONS: Daily consumption of low-fat plant sterol dairy product favourably changes lipid profile by reducing LDL-cholesterol, and may also have an anti-oxidative effect through a reduction of plasma isoprostanes.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis]. / Linee guida per la diagnosi, prevenzione e terapia dell'osteoporosi Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro - SIOMMMS.

UNLABELLED: The guidelines for the osteoporosis management were first drafted by a working group and then critically evaluated by the board of SIOMMMS. The most relevant points are: DEFINITION: Osteoporosis is defined as a quantitative and qualitative deterioration of bone tissue leading to increased risk of fracture. Postmenopausal and senile osteoporosis are defined as primitive. DIAGNOSIS: The cornerstone for the diagnosis of osteoporosis is the measurement of bone mineral density (BMD) by DXA (dual-energy X-ray absortiometry) at the femoral neck with T-score values <-2.5, following the WHO definition. Other DXA sites or technologies for measuring bone mass are also acceptable when the former is not accessible. A BMD evaluation is recommended to all women above 65 years of age. At younger age or in man the bone assessment is recommended only in subjects with specific risk factors. A control of bone mass measurement is seldom required before 2 years. DIFFERENTIAL DIAGNOSIS: A few biochemical tests such as serum and urinary calcium, protein electrophoresis, serum creatinine and ESR are usually sufficient to exclude most secondary types of osteoporosis. The value of the so called bone turnover markers for the diagnosis and follow-up of osteoporosis remains uncertain. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management. PREVENTION: The osteoporosis prevention should be based on the elimination of specific risk factors such as inadequate calcium and vitamin D intake, smoking and sedentary life. The use of pharmacological agents in subjects with BMD values >-2.5 is usually not justified. Pharmacological intervention: The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk. This is the case only when the risk of fracture is rather high. FRAX is recognized as a useful tool for easily estimate the long-term fracture risk. SIOMMMS with these guidelines is committed to validate and further develop this diagnostic tool.

Retroperitoneal abscess: an uncommon localization of tubercular infection.

We describe a rare case of a 29-year-old immunocompetent Nigerian male affected by an abdominal abscess due to Mycobacterium tuberculosis infection. Diagnosis was achieved with cultures from surgical drainage. No pulmonary, renal, or gastrointestinal involvement was identified. The patient was successfully treated with standard four-drug antitubercular therapy.

Renal dysfunction predicts long-term mortality in patients with lower extremity arterial disease.

BACKGROUND: Patients with renal insufficiency tend to suffer from advanced atherosclerosis and exhibit a reduced life expectancy. OBJECTIVES AND DESIGN: This prospective study investigated the relation between renal dysfunction and long-term all-cause and cardiovascular mortality in a population of nonsurgical patients with lower extremity arterial disease (LEAD). SUBJECTS AND METHODS: A total of 357 patients with symptomatic LEAD underwent baseline glomerular filtration rate (GFR) estimation by the 4-variable Modification Diet in Renal Diseases equation, and were then followed for 4.2 years (range: 1-17). RESULTS: During follow-up, 131 patients died (8.6 deaths per 100 patient-years), 79 of whom (60%) from cardiovascular causes. All-cause death rates were 3.8, 6.6, and 15.5 per 100 patient-years, respectively, in the groups with normal GFR, mild reduction in GFR (60-89 mL min(-1) per 1.73 m2) and chronic kidney disease (CKD; <60 mL min(-1) per 1.73 m2; P < 0.001 by log-rank test). Compared to patients with normal renal function, the risk of all-cause and cardiovascular death was significantly higher in patients with CKD [hazard ratio, respectively, 2.23, 95% confidence interval (CI): 1.16-4.34, P = 0.017; 2.15, 95% CI: 1.05-4.43, P = 0.03]. The association of CKD with all-cause and cardiovascular mortality were independent of age, LEAD severity, cardiovascular risk factors and treatment with angiotensin-converting enzyme (ACE)-inhibitors, hypolipidaemic and antiplatelet drugs. The power of GFR in predicting all-cause death was higher than that of ankle-brachial pressure index (P = 0.029) and Framingham risk score (P < 0.0001). CONCLUSION: Chronic kidney disease strongly predicts long-term mortality in patients with symptomatic LEAD irrespective of disease severity, cardiovascular risk factors and concomitant treatments.

Natriuretic peptides levels are related to HDL-cholesterol with no influence on endothelium dependent vasodilatation.

BACKGROUND: The natriuretic peptides, Brain Natriuretic Peptide (BNP), C-type Natriuretic Peptide (CNP), are mediators of cardiovascular homeostasis. The impairment of arterial ability to vasodilate, also known as endothelial dysfunction, represents the first stage of atherosclerotic damage and may be assessed as brachial flow mediated vasodilation (FMV) in human. Generally an altered brachial FMV is documented in association to several cardiovascular risk factors as hypercholesterolemia. Aim of the study was to evaluate the behaviour of BNP and CNP in hyperlipemia and the potential relationship to FMV. PATIENTS AND METHODS: Forty-four hyperlipemic patients (LDL-cholesterol > 130 mg/dl and/or triglycerides > 150, age 35-60 y) of both genders and 20 normolipemic patients, matched for age and sex were investigated. RESULTS: Patients had lower values of brachial FMV in comparison to controls (3.9 +/- 3.5 vs 7.5 +/- 0.5%, p < 0.005), no differences were observed in BNP (4.6 +/- 4.6 vs 5.9 +/- 3.4 ng/mL, p = n.s) and CNP (4.1 +/- 5.8 vs 5.7 +/- 3.3 ng/mL, p = n.s). Univariate analysis showed a positive correlation between BNP and HDL-cholesterol values (r = 0.36, p = 0.001). In the multivariate analysis, LDL-cholesterol (beta = -0.57), HDL-cholesterol (beta = 0.26) and brachial artery diameter (beta = -0.33) were predictors of brachial FMV. The only predictive variable for CNP was HDL-cholesterol (beta = 0.37). CONCLUSIONS: The present study suggested that natriuretic peptides, BNP and CNP, are not altered in patients affected by hypercholesterolemia. Nevertheless, the levels of HDL-cholesterol are strictly related to the values of CNP. This observation, in humans, adds another mechanism to the vascular control exerted by HDL.

Brain natriuretic peptide as a cardiac marker of transient radiotherapy-related damage in left-sided breast cancer patients: A prospective study.

PURPOSE: Our study evaluated brain natriuretic peptide (BNP) changes over time after adjuvant radiotherapy (RT) in women with left-sided breast cancer investigating its correlation with heart dosimetric parameters. METHODS: Forty-three patients underwent clinical cardiac examination, electrocardiogram (ECG), echocardiography and BNP measurement before RT (T0) and 1 (T1), 6 (T6) and 12 months (T12) after. After T12 cardiac assessment was performed annually in each patient. Mean values and standard deviation (SD) of BNP, left ventricular ejection fraction (LVEF), V20, V25, V30, V45 and mean dose were calculated. Normalized BNP (BNPn) was calculated as follows: BNPnT1 = BNPT1/BNPT0, BNPnT6 = BNPT6/BNPT0, BNPnT12 = BNPT12/BNPT0. Absolute BNP and BNPn values were used for data analysis. RESULTS: Median follow-up from the end of RT to the last check-up was 87 months (range 37-120 months). Minimum follow-up was 74 months except for two patients, who died at respectively 37 and 47 months after RT. In all patients LVEF did not change significantly (p = 0.22) after RT. BNP increased significantly (p < 0.001), particularly 1 and 6 months after RT. It slightly decreased after 12 months. BNP did not correlate with V20, V25, V30, V45, mean dose and MHD. All BNPn correlated significantly (p < 0.05) with V20, V25, V30, V45, mean dose and MHD. Four patients had a cardiac event; in the only subject who developed myocardial infarction, V20, V25, V30 and V45 were the highest and BNP increased from T1 and persisted high even at T12. CONCLUSION: Our results confirm that BNP could be a useful minimally invasive marker of early RT related cardiac impairment.

The treatment of recurrent brain metastases with stereotactic radiosurgery.

Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy.

Physiological increments in plasma insulin concentrations have selective and different effects on synthesis of hepatic proteins in normal humans.

These studies tested the hypothesis that physiological increments in plasma insulin concentrations have selective effects on the synthesis of hepatic proteins in humans. Leucine kinetics and fractional synthetic rates of albumin, fibrinogen, antithrombin III, and apoB-100 were determined in 6 normal subjects, on two different occasions during either the infusion of saline (control study) or a euglycemic-hyperinsulinemic (0.4 mU.kg-1 x min-1 for 240 min) clamp, by a primed-constant infusion of [1-14C]Leu. The insulin infusion significantly decreased the rates of nonoxidative Leu disposal (1.70 +/- 0.10 vs. control 2.06 +/- 0.09 mol.kg-1 x min-1), increased the albumin (7.2 +/- 0.4 vs. 6.2 +/- 0.6%/day), decreased the fibrinogen (18 +/- 1 vs. 23 +/- 2%/day), and antithrombin III (28 +/- 3 vs. 40 +/- 4%/day) fractional synthetic rate, whereas it did not affect the total apoB-100 (49 +/- 5 vs. 52 +/- 6%/day) fractional synthetic rate. Thus, the insulin-induced decrement in the estimates of whole-body protein synthesis (nonoxidative Leu disposal) represents the mean result of opposite effects of hyperinsulinemia on the synthesis of proteins with different functions. The positive effect of insulin on albumin synthesis may play an important anabolic role during nutrient absorption by promoting the capture of a relevant amount of dietary essential amino acids into the protein, whereas the negative effect of insulin on fibrinogen synthesis might, at least partially, account for the increased plasma fibrinogen concentrations previously reported in poorly controlled diabetic patients.