[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

Bevacizumab-associated hyperlipoproteinemia type IIb in a patient with advanced invasive-ductal breast cancer.

AIM: We report a case of bevacizumab-associated hyperlipoproteinemia in a patient with advanced breast cancer. CASE SUMMARY: A 57-year-old woman with advanced invasive-ductal breast cancer was administered bevacizumab from March 2008 to February 2009. Pretreatment laboratory showed borderline hypercholesterolemia (5.1 mmol/L, 197 mg/dL) and normal triglycerides (1.3 mmol/L, 115 mg/dL). Three months on treatment with bevacizumab, both serum cholesterol (11.9 mmol/L, 460 mg/dL) and triglycerides (7.4 mmol/L, 655 mg/dL) increased substantially, and remained well above the normal range for a period of bevacizumab treatment. From March 2008 to August 2008, the patient also received anticancer treatment with liposomal doxorubicin that was stopped early due to hand-foot syndrome. No concurrent hyperlipidemic drugs have been taken by the patient at the time of bevacizumab treatment. In February 2009, bevacizumab was stopped and the patient went on to receive paclitaxel for hepatic tumor progression. By December 2009, both serum triglycerides (1.3 mmol/L, 115 mg/dL) and cholesterol (3.2 mmol/L, 123 mg/dL) had normalized. DISCUSSION: This is the first published case of bevacizumab-associated hyperlipoproteinemia. By applying the Naranjo ADR probability scales, at least a possible relationship between hyperlipoproteinemia type IIb and bevacizumab in this patient is supported by the data (Naranjo score 4). No hyperlipidemic drugs were given concurrently with bevacizumab, and the serum cholesterol and triglycerides decreased quickly after bevacizumab was discontinued. CONCLUSIONS: This study describes a case of bevacizumab-associated hyperlipidemia. Patients receiving bevacizumab should have their cholesterol and triglycerides checked for potential worsening.

Procollagen type I N-propeptide is a predictor of skeletal morbidity in patients with malignant osteolytic bone disease on bisphosphonates.

BACKGROUND: There is an urgent need for individualized treatment of malignant bone disease (MBD), as the clinical benefit from bone-targeted therapies is moderate. We assessed the predictive value of the bone formation marker procollagen type I N-propeptide (PINP) for skeletal morbidity in patients with MBD receiving pamidronate. METHODS: Seventy patients with advanced MBD were randomized to receive pamidronate 60 mg (n = 35) or 90 mg (n = 35) every 3 weeks for six cycles in a double-blind study. PINP was analyzed at baseline and before each administration of pamidronate, using a validated ELISA. Serum PINP concentrations were compared with pain response (visual analog scale VAS, composite pain score) and skeletal morbidity (skeletal-related events, SRE) using Student's T-test, Wilcoxon rank-sum and log-rank test, respectively. RESULTS: Patients with ≥20% pain reduction in the VAS had lower baseline PINP concentrations when compared to patients with <20% VAS response (P < 0.0001). A high baseline serum PINP concentration (highest tertile versus lower two tertiles) was significantly associated with a shorter duration of pain response (P < 0.0001) and a shorter time interval to first SRE (P < 0.008). Sensitivity of a low baseline PINP serum concentration for freedom from SRE at 1 year from randomization was 75% (15 out of 20 patients), while specificity was 82% (27 out of 33 patients). CONCLUSIONS: Serum PINP has been shown to be a significant predictor for skeletal morbidity in patients with MBD on pamidronate treatment. Prospective validation of PINP in patients with MBD to assess the prognosis or individualize bone-targeted treatment is justified.

Role of RAS inhibition in the regulation of Cu/Zn-SOD in the cardiac and peripheral arterial beds in humans.

Inhibition of the renin-angiotensin system (RAS) improves hemodynamics and may ameliorate oxidative stress in heart failure (HF). Through activation of nicotinamide adenine dinucleotide phosphate oxidase, angiotensin II induces superoxide, which is primarily cleared by cytosolic copper-zinc superoxide dismutase (Cu/Zn-SOD). We examined the interdependency of hemodynamics and levels of Cu/Zn-SOD and oxidized low-density lipoprotein (oxLDL) in HF patients, using a randomized, double-blinded, crossover design to compare (i) the outcomes of single-agent therapy with either benazepril or valsartan alone vs. the combination thereof and (ii) the outcome of single-agent treatment with benazepril vs. single-agent treatment with valsartan. After each treatment, arterial (ART) and coronary sinus (CS) blood samples were collected. Cu/Zn-SOD and oxLDL levels were higher in CS samples than in ART samples. Furthermore, patients under combined treatment exhibited the highest CS levels of Cu/Zn-SOD, whereas there was no significant difference between the groups on either benazepril or valsartan alone. This finding suggests an augmentation of the cardiac antioxidative potential under more complete RAS inhibition. Cu/Zn-SOD and oxLDL levels correlated with measures of afterload rather than preload, which in turn suggests a beneficial effect of afterload reduction on oxidative stress in HF.

Combining bone resorption markers and heel quantitative ultrasound to discriminate between fracture cases and controls.

SUMMARY: This nested case-control analysis of a Swiss ambulatory cohort of elderly women assessed the discriminatory power of urinary markers of bone resorption and heel quantitative ultrasound for non-vertebral fractures. The tests all discriminated between cases and controls, but combining the two strategies yielded no additional relevant information. INTRODUCTION: Data are limited regarding the combination of bone resorption markers and heel quantitative bone ultrasound (QUS) in the detection of women at risk for fracture. METHODS: In a nested case-control analysis, we studied 368 women (mean age 76.2 +/- 3.2 years), 195 with low-trauma non-vertebral fractures and 173 without, matched for age, BMI, medical center, and follow-up duration, from a prospective study designed to predict fractures. Urinary total pyridinolines (PYD) and deoxypyridinolines (DPD) were measured by high performance liquid chromatography. All women underwent bone evaluations using Achilles+ and Sahara heel QUS. RESULTS: Areas under the receiver operating-characteristic curve (AUC) for discriminative models of the fracture group, with 95% confidence intervals, were 0.62 (0.56-0.68) and 0.59 (0.53-0.65) for PYD and DPD, and 0.64 (0.58-0.69) and 0.65 (0.59-0.71) for Achilles+ and Sahara QUS, respectively. The combination of resorption markers and QUS added no significant discriminatory information to either measurement alone with an AUC of 0.66 (0.60-0.71) for Achilles+ with PYD and 0.68 (0.62-0.73) for Sahara with PYD. CONCLUSIONS: Urinary bone resorption markers and QUS are equally discriminatory between non-vertebral fracture patients and controls. However, the combination of bone resorption markers and QUS is not better than either test used alone.

[Update of lipid lowering therapy]. / Update der lipidsenkenden Therapie.

Dyslipidemia is one of the most important cardiovascular risk factors. Accordingly preventive measures to normalize lipids are of great importance. The indication for a lipid lowering therapy according to current guidelines focuses on the identification of a patient's global risk, i.e. the contribution of all major cardiovascular risk factors. The selection of the lipid lowering therapy should be appropriate for the kind of lipid disorder. This may be a special challenge with respect to target values and safety aspects. Statins in monotherapy are generally considered safe drugs. Higher dosages may be associated with liver toxicity and muscle problems. Lifestyle management should underpin all lipid management strategies.

N-terminal pro-brain natriuretic peptide used for the prediction of coronary artery stenosis.

BACKGROUND: The level of the inactive N-terminal fragment of pro-brain (B-type) natriuretic peptide (NT-proBNP) is a prognostic marker in patients with acute and chronic coronary artery disease (CAD). It might also be valuable for non-invasive diagnosis of coronary artery disease. MATERIALS AND METHODS: The NT-proBNP was measured in 781 consecutive patients with normal left ventricular function referred for coronary angiography owing to symptoms or signs of CAD. The diagnostic value of NT-proBNP was assessed for predicting CAD at angiography. RESULTS: Elevated NT-proBNP levels were associated with the extent of CAD and with the female sex (P < 0.001). The ability of NT-proBNP to predict significant coronary disease at angiography was assessed separately for men using a cut-off point of 85 pg mL(-1), positive likelihood ratio 2.2 (95% CI, 1.7-3.0), negative likelihood ratio 0.53 (95% CI 0.45-0.63) and area under the receiver-operating-characteristic (ROC) curve 0.72: for women, it was assessed using a cut-off point of 165 pg mL(-1), positive likelihood ratio 2.4 (95% CI, 1.7-3.4), negative likelihood ratio 0.55 (95% CI, 0.44-0.70) and area under ROC curve 0.71. In multiple logistic-regression analysis, NT-proBNP added significant independent predictive power to other clinical variables in models predicting CAD (odds ratio 2.76, 95% CI, 1.76-4.32, P < 0.001). CONCLUSIONS: The NT-proBNP is a marker of non-obstructive CAD and of significant coronary stenosis. In conjunction with other clinical information, measurement of NT-proBNP with the use of sex-specific reference ranges may improve the non-invasive prediction of CAD.

Hypertriglyceridemia as a possible risk factor for prostate cancer.

We retrospectively studied anthropometric and laboratory parameters (including serum triglycerides, cholesterol), as well as comedication in 504 patients diagnosed with prostate cancer between January 1997 and August 2002 at a single referral center, and compared these patients with 565 age-matched patients with benign prostatic hyperplasia. A positive correlation was found between serum triglycerides and prostate cancer (odds ratio: 1.148/mmol/l; 95% confidence interval (CI) 1.003-1.315; P<0.05) after correcting for age, body mass index, diabetes and comedication with statins. Hypertriglyceridemia may increase the risk of prostate cancer, and the prognostic relevancy of serum triglycerides should be studied prospectively.

Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country.

BACKGROUND: The prevalence of hyperuricemia has rarely been investigated in developing countries. The purpose of the present study was to investigate the prevalence of hyperuricemia and the association between uric acid levels and the various cardiovascular risk factors in a developing country with high average blood pressures (the Seychelles, Indian Ocean, population mainly of African origin). METHODS: This cross-sectional health examination survey was based on a population random sample from the Seychelles. It included 1011 subjects aged 25 to 64 years. Blood pressure (BP), body mass index (BMI), waist circumference, waist-to-hip ratio, total and HDL cholesterol, serum triglycerides and serum uric acid were measured. Data were analyzed using scatterplot smoothing techniques and gender-specific linear regression models. RESULTS: The prevalence of a serum uric acid level >420 micromol/L in men was 35.2% and the prevalence of a serum uric acid level >360 micromol/L was 8.7% in women. Serum uric acid was strongly related to serum triglycerides in men as well as in women (r = 0.73 in men and r = 0.59 in women, p < 0.001). Uric acid levels were also significantly associated but to a lesser degree with age, BMI, blood pressure, alcohol and the use of antihypertensive therapy. In a regression model, triglycerides, age, BMI, antihypertensive therapy and alcohol consumption accounted for about 50% (R2) of the serum uric acid variations in men as well as in women. CONCLUSIONS: This study shows that the prevalence of hyperuricemia can be high in a developing country such as the Seychelles. Besides alcohol consumption and the use of antihypertensive therapy, mainly diuretics, serum uric acid is markedly associated with parameters of the metabolic syndrome, in particular serum triglycerides. Considering the growing incidence of obesity and metabolic syndrome worldwide and the potential link between hyperuricemia and cardiovascular complications, more emphasis should be put on the evolving prevalence of hyperuricemia in developing countries.

Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media.

BACKGROUND: The delayed increase of creatinine after radiocontrast application is a potential reason for overlooking radiocontrast nephrotoxicity. Cystatin C may be more useful to rapidly assess a decrease in glomerular filtration rate (GFR). We compared cystatin C and creatinine to examine their kinetics after application of radiocontrast media. PATIENTS AND METHODS: Forty-one patients (60.8 +/- 8.8 years, 68% males) with normal to subnormal GFR scheduled for coronary angiography (27% with angioplasty), were studied for serum cystatin C and creatinine levels before, 5 h, 24 h and 48 h after angiography. Furthermore, alpha1-microglobulin was checked for evidence of tubular damage. RESULTS: At 5 hours after angiography, there was no significant change compared to baseline in either serum creatinine nor cystatin C. In comparison with the value immediately before coronary angiography, the increase of cystatin C achieved a maximum at 24 h after the application of the contrast agent (+7.2%). Within 48 h, cystatin C decreased to the level before angiography. Serum creatinine increased at 24 h (+7.7%) and continued to increase at 48 h (+11.3%). CONCLUSION: Cystatin C increases earlier after radiocontrast application compared with creatinine. Therefore, cystatin C needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of cystatin C in respect of an earlier detection of radiocontrast nephrotoxicity.

Short-term effects of atorvastatin on C-reactive protein.

AIM: To study the short-term effect of atorvastatin on C-reactive protein (CRP) in patients with or at risk for coronary heart disease. METHODS AND RESULTS: One hundred and fifty-five randomly selected patients from the SWiss Intervention Trial for lowering CHolesterol (SWITCH) were assessed for high sensitivity CRP, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides at baseline, and after 1 and 3 months of treatment with atorvastatin at various doses to reach pre-defined lipid target values. The median decrease of cholesterol was 28% after 1 month and 35% after 3 months. LDL-cholesterol was decreased by 37% and 45%, HDL-cholesterol was increased by 7% and 8%, respectively. Patients with a low CRP baseline concentration (lowest quartile <1.34 mg. l(-1)) displayed no significant change, whereas patients in the other quartiles showed a significant decrease, of 22% to 40% (P -value <0.05 to <0.001) at 1 month and of 32% to 36% after 3 months compared to baseline. The decrease in CRP lowering was thus fully established by 1 month and this response was independent of lipid and lipoprotein changes as well as atorvastatin doses. CONCLUSION: Atorvastatin significantly decreases CRP concentrations after 4 weeks of therapy. These results may be important with respect to the early benefit of statin therapy.

Comparability of serum and plasma concentrations of haemostasis activation markers.

Since serum and plasma D-dimer concentrations correlate very well, we evaluated the comparability of other haemostasis activation markers in plasma and serum. Prothrombin fragment F1+2, fibrin monomer and D-dimer concentrations were measured with commercially available immunoassays in serum and plasma. Serum to plasma ratios were evaluated to determine the direct (prothrombin fragment F1+2) and indirect (fibrin monomer, D-dimer) downstream influence of prothrombinase on the serum to plasma comparability. Prothrombin fragment F1+2 serum and plasma concentrations did not correlate (R2 = 0.09, ns), while an unexpected high degree of correlation was found for fibrin monomer (R2 = 0.66, p < 0.001), and, as expected, a very good correlation was found for D-dimer (R2 = 0.94, p < 0.001). Median serum to plasma ratios decreased from prothrombin fragment F1+2 (16.26) to fibrin monomer (2.24, p < 0.001) and D-dimer (1.00, p < 0.001), following a highly linear relationship (R2 = 0.93) Plasma and serum concentrations of the evaluated markers correlate the better the farther from prothrombinase activity the respective marker is generated. Serum is not suitable for prothrombin fragment F1+2 measurements, whereas fibrin monomer serum concentrations seem of value for research applications. With the used assay, serum seems an appropriate matrix for clinical D-dimer measurements. This would considerably simplify testing strategies. Validation in further clinical trials is needed.

Premature atherosclerosis in HIV-infected individuals--focus on protease inhibitor therapy.

OBJECTIVE: Lipid disorders associated with the use of protease inhibitors may contribute to the premature development of atherosclerosis. The purpose of the present study was to determine whether the administration of a protease inhibitor-containing regimen to middle-aged (30-50 years) HIV-infected individuals for 6 months or longer is associated with an increased prevalence of atherosclerosis. METHODS: High-resolution B-mode ultrasound imaging was used to visualize the femoral and carotid arteries of 68 HIV-negative and 168 HIV-infected individuals, including 136 patients who had received protease inhibitors for 26.8 +/- 8.9 months (mean +/- SD). Atherogenic plaques were defined as a thickening of the intima-media > or = 1200 mm. RESULTS: The proportion of participants with one or more plaques was higher in the HIV-infected group in comparison with the HIV-negative group (55 versus 38%; P = 0.02), and so was the prevalence of cigarette smoking (61 versus 46%; P = 0.03) and hyperlipidaemia (56 versus 24%; P < 0.001). The presence of plaque was independently associated with age, male gender, plasma low-density lipoprotein cholesterol levels and smoking. In univariate logistic regression analysis, an association was also found with HIV infection. Among HIV-infected subjects protease inhibitor therapy was not associated with the presence of plaque. CONCLUSIONS: A large proportion of the middle-aged HIV-infected individuals examined during this study had one or more atherosclerotic plaques within the femoral or carotid arteries. The presence of peripheral atherosclerosis within this population is not associated with the use of protease inhibitors, but rather with 'classic' cardiovascular risk factors such as smoking and hyperlipidaemia, which are amenable to interventions.

Alterations of lipolytic enzymes and high-density lipoprotein subfractions induced by physical activity in type 2 diabetes mellitus.

OBJECTIVE: This study investigates the effects of regular moderate physical activity on lipolytic enzymes and plasma lipid concentration, particularly high-density lipoprotein cholesterol (HDL-C) subfractions, in patients with type 2 diabetes mellitus. DESIGN: Ten patients participated in a 3-month exercise programme without any changes in current medical therapy. The control group consisted of six patients who were matched with regard to sex, age, diabetes duration and diabetes therapy. RESULTS: Mean (+/- SE) physical activity in the intervention group increased from 70 +/- 21 to 220 +/- 28 min per week, which resulted in an increase in total HDL-C from 1.04 +/- 0.07 to 1.28 +/- 0.12 (P < 0.001). The HDL3-C subfraction increased from 0.71 +/- 0.08 to 0.86 +/- 0.08 mM (P = 0.01) with no significant changes in the HDL2-C subfraction (0.33 +/- 0.04 vs. 0.42 +/- 0.05). These changes were paralleled by an 85% increase in hepatic lipase (HL) activity, from 25.7 +/- 5.1 to 47.4 +/- 4.9 micromol x mL(-1) x h(-1) (P < 0.001) and a 45% increase in lipoprotein lipase (LPL) activity, from 16.8 +/- 3.0-24.3 +/- 2.7 micromol x mL(-1) x h(-1) (P = 0.01). Lecithin-cholesterol acyl-transferase (LCAT) activity increased by 32%, from 156 +/- 26 to 206 +/- 32 nmol x mL(-1) x h(-1) (P < 0.001). In the control group there were no significant changes in any of the variables assessed. CONCLUSIONS: Regular moderate physical activity in patients with type 2 diabetes led to an overall increase in HL, LPL, and LCAT. HL showed a more pronounced increase than LPL and LCAT. The changes in lipolytic and transferase enzyme pattern resulted in a significant increase of plasma HDL-C, mainly of the HDL3-C subfraction.

Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients.

Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (i.e., angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ((HCO3)p decreased from 19.8+/-0.4 mmol/L to 17.7+/-0.6 mmol/L, P<.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P<.005), urinary anion gap (+31 mEq/day, P<.05), and sulfate excretion (+32 mEq/day, P<.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P<.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P<.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ((HCO3)p decreased to 15.7+/-0.4 mmol/L, P<.05) and hyperkalemia (5.0 mmol/L, P<.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P<.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism.