Effect of angiotensin II receptor blockers, candesartan, on osteoprotegerin level in hypertensive patients: Link between bone and RAAS.

INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) has recently been considered as a possible link between bone and vascular disease. The present study was designed to determine the effect of the angiotensin II receptor blocker candesartan on circulating osteoprotegerin (OPG) in hypertensive patients with multiple cardiovascular risk factors. MATERIAL AND METHODS: A total of 69 hypertensive patients were randomized to two groups: Group 1 included patients treated with oral candesartan in doses of 16 mg to 32 mg per day in addition to routine standard of care (routine care + ARB), and Group 2 included patients who received routine standard of care other than ARBs or ACEIs, with no change to their treatment (routine care). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin, homeostasis model assessment-insulin resistance (HOMA-IR) and OPG. RESULTS: Baseline OPG levels did not differ significantly by treatment group. Post-treatment serum OPG levels were marginally lower in Group1 compared with Group 2; however, this decrease did not reach statistical significance (p = 0.077). CONCLUSIONS: In the present study, treatment with the ARB candesartan had no significant effect on circulating OPG levels in hypertensive patients with multiple cardiovascular risk factors. To the best of our knowledge, the present study is the first to estimate an effect of candesartan on bone remodeling marker such as OPG.

Does metformin treatment influence bone formation in patients with nonalcoholic fatty liver disease?

Antidiabetic drug metformin that improves insulin sensitivity and used in the treatment of nonalcoholic fatty liver disease (NAFLD), may affect the bone health. Our study was designed to investigate a possible effect of metformin on bone formation marker, procollagen type I N-terminal propeptide (P1NP) in patients with NAFLD.In a randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of 2 groups: Group 1 received daily metformin and Group 2 received placebo. Metabolic parameters, insulin resistance markers, and P1NP were determined.Although circulating P1NP levels did not differ significantly between the groups at baseline, at the end of the study, P1NP was significantly lower in patients treated with metformin than in the placebo group (p<0.007). Within-group analysis indicated that P1NP levels significantly decreased (p=0.023) in patients receiving metformin during 4-month follow-up period, while no change in P1NP was observed in placebo group (p=0.359). In general linear model metformin treatment was the only significant independent predictor of endpoint P1NP.Metformin treatment was associated with decrease in P1NP levels in patients with NAFLD. The effect on P1NP was independent of glucose lowering effect and caused from exposure to metformin per se.

Relation of adiponectin to glucose tolerance status, adiposity, and cardiovascular risk factor load.

OBJECTIVE: Adiponectin has anti-atherogenic and anti-inflammatory properties. We investigated the influence of adiponectin on glucose tolerance status, adiposity and cardiovascular risk factors (CVRFs). DESIGN AND PATIENTS: Study consisted of 107 subjects: 55 with normal glucose tolerance (NGT) and 52 with impaired glucose regulation (IGR) who were divided into two groups: 24 subjects with impaired fasting glucose (IFG Group) and 28 patients with type 2 diabetes mellitus (DM Group). In additional analysis, study participants were divided into two groups, according to CVRFs: low and high risk. MEASUREMENTS: Patients were evaluated for glucose, HbA1C, insulin, lipids, CRP, HOMA-IR and adiponectin. RESULTS: Adiponectin was significantly higher in NGT group than in IFG (P = 0.003) and DM (P = 0.01) groups. Adiponectin was significantly, positively associated with HDL and inversely associated with glucose, HbA1c, ALT, AST, TG, HOMA-IR. Patients with higher CVRFs load have lesser adiponectin compared to patients with low cardiovascular risk P < 0.0001). Adiponectin was inversely associated with the number of risk factors (r = -0.430, P = 0.0001). CONCLUSIONS: Circulating adiponectin was significantly lower in subjects with different degree of IGR compared to subjects with normal glucose homeostasis. Adiponectin was significantly lower in high risk group than low risk group and decreased concurrently with increased number of CVRFs.

Adiponectin and vascular properties in obese patients: is it a novel biomarker of early atherosclerosis?

OBJECTIVES: Adiponectin is an adipocyte-derived collagen-like protein, highly specific to adipose tissue and may represent an important link between obesity and atherosclerosis. The present study was designed to investigate a possible association between serum adiponectin levels and early vascular changes in obese patients as determined by intima media thickness (IMT) and arterial pulse-wave contour analysis. DESIGN: Obese subjects (n=47) were evaluated for arterial structure and function, metabolic parameters and serum adiponectin levels. MEASUREMENTS: IMT was measured by ultrasound. Arterial elasticity was evaluated using pulse-wave contour analysis. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). RESULTS: diponectin was significantly, inversely associated with mean IMT (r=-0.369, P=0.011) and significantly positively associated with large artery elasticity index (LAEI) (r=0.467, P=0.001) as well as small artery elasticity index (SAEI) (r=0.462, P=0.001). In separate multivariate models, adiponectin remained significantly associated with mean IMT, LAEI and SAEI even after adjustment for cardiovascular confounders. Among metabolic parameters, adiponectin was significantly positively associated with HDL cholesterol and inversely associated with triglycerides. Adiponectin was significantly inversely associated with fasting insulin and HOMA-IR. In addition, a marginally inverse association between adiponectin and ALT was observed. CONCLUSIONS: In this study, serum adiponectin levels were significantly associated with indices of subclinical atherosclerosis, such as IMT and arterial compliance in obese patients. This association was independent of traditional cardiovascular risk factors.

Osteoprotegerin as an independent marker of subclinical atherosclerosis in osteoporotic postmenopausal women.

Osteoprotegerin (OPG) appears to represent the molecular link between bone resorption and vascular calcification, and may help to explain the high prevalence of atherosclerosis and osteoporosis in postmenopausal women. We investigated a possible association between serum OPG levels and arterial stiffness in postmenopausal women with osteoporosis. 70 postmenopausal women with osteoporosis and cardiovascular risk factors but without coronary artery disease were evaluated for metabolic, inflammatory parameters and serum OPG levels. Pulse wave velocity (PWV) and augmentation index (AIx) were performed as a simple noninvasive recording of the two artery sites pressure waveform using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). Serum OPG levels were significantly, positively associated with AIx (r=0.39, p=0.003) and with PWV (r=0.81, p<0.0001). No association between OPG levels and hemodynamic variables or measures of glucose metabolism was observed. Among inflammatory markers, OPG was significantly, positively associated with fibrinogen (r=0.323, p=0.015). In a multiple linear regression analysis, OPG was independent predictor of PWV (standardized beta=0.75, p<0.0001) and AIx (standardized beta=0.41, p=0.01). Serum OPG is potentially an independent predictor of early vascular adverse changes in osteoporotic postmenopausal women.

Effect of long-term treatment with risedronate on arterial compliance in osteoporotic patients with cardiovascular risk factors.

Accumulating evidence suggests that osteoporosis and coronary artery disease have epidemiologic similarities. Moreover, the anti-atherogenic effects of bisphosphonates have been observed in vitro and in animal models. The present study investigated the effect of risedronate on indices of arterial compliance, serum osteoprotegerin (OPG) level, inflammatory and metabolic parameters in osteoporotic women with cardiovascular risk factors. In an open label, prospective study 68 postmenopausal osteoporotic women were evaluated for the study. Patients received risedronate orally in a dose of 35 mg per week, daily supplements of calcium and cholecalciferol during 6month treatment period. Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, fibrinogen, hs-CRP and plasma osreoprotegerin. Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota). Large artery elasticity index (LAEI) increased from 9.86+/-3.66 to 11.54+/-">+/-3.16 ml/mm HgX10 (p<0.0001) during treatment period. Small artery elasticity index (SAEI) increased from 2.64+/-1.10 to 3.28+/-1.16 ml/mm HgX100 (p<0.0001). Systemic vascular resistance (SVR) decreased from 1876.12+/-457.72 to 1646.12+/-260.17 dyn/s/cm(- 5) (p<0.013). Metabolic parameters did not change during the treatment period. Plasma osteoprotegerin was significantly, positively correlated to SVR at baseline (r=0.36, p=0.045). At the final visit, OPG was marginally inversely associated with LAE (r=- 0.312, p=0.09), and significantly, positively associated with total vascular impedance (r=0.43, p=0.015). In conclusion, prolonged treatment with risedronate improved arterial elasticity of small and large arteries, and decreased SVR. These beneficial vascular effects were not related to changes in cardiovascular risk factors and may be attributed to direct effects of risedronate on the vascular wall.

Effect of homocysteine-lowering therapy on arterial elasticity and metabolic parameters in metformin-treated diabetic patients.

Metformin may affect the risk of atherothrombotic disease. However, metformin increases levels of homocysteine (Hcy), considered an independent risk factor for atherosclerosis. We evaluate whether homocysteine-lowering has a beneficial effect on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. In double-blind, placebo-controlled study, 60 diabetic patients treated with high dose of metformin were randomly assigned to receive daily oral supplementation with folate (1000 mcg), vitamins B12 (400 mcg) and B6 (10mg) (group 1) or placebo (group 2). Lipid profile, HbA1C, insulin, C-peptide, hs-CRP, vitamin B12, folic acid, homocysteine, endothelin, homeostasis model assessment-insulin resistance (HOMA-IR) were measured. Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, MN). The two groups were similar at baseline in terms of hemodynamic and arterial elasticity parameters. After a 4-month small artery elasticity index (SAEI) was significantly greater in patients who received Hcy-lowering agents than in the placebo group: 4.3+/-2.04 ml/mm Hg x 100 versus 3.2+/-1.1 ml/mm Hg x 100, p=0.01. Post-treatment vitamin B12 and folic acid levels were greater in group 1 versus group 2: 738.1+/-279.9 pg/ml versus 566.1+/-167.4 pg/ml, p=0.007 and 14.9+/-4.8 ng/ml versus 8.3+/-2.9 ng/ml, p<0.0001, respectively. Hcy level decreased significantly in the treatment group from 10.0+/-4.4 to 7.6+/-2.5 micromol/l, p=0.002 and did not change in placebo group (p=0.9). Hcy-lowering therapy improved small arterial elasticity in diabetic patients treated with high dose of metformin. The improvement was associated with a decrease in Hcy as well as an increase in folic acid and vitamin B12. These findings suggest that Hcy-lowering may have beneficial vascular effect in metformin-treated diabetic patients.

High dose treatment with angiotensin II receptor blocker in patients with hypertension: differential effect of tissue protection versus blood pressure lowering.

Aggressive inhibition of renin-angiotensin-aldosterone system may provide the best cardiovascular protection. We examined the effect of different doses of angiotensin II receptor blocker, Candesartan, on arterial elasticity, inflammatory and metabolic parameters in hypertensive patients with multiple cardiovascular risk factors. 69 hypertensive patients were randomized into three groups: group 1 included patients treated with high doses of Candesartan (32 mg), group 2 included patients treated with conventional doses of Candesartan (16 mg), group 3 included patients that received antihypertensive treatment other that angiotensin II type-1 receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, hs-CRP, aldosterone, renin and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity was evaluated using pulse wave contour analysis method (HDI CR 2000, Eagan, Minnesota). In patients treated with high doses of Candesartan: large artery elasticity index (LAEI) increased from 8.6+/-2.8 to 16.6+/-5.1 ml/mm Hg x 100 after 6 months of treatment (p<0.0001). Small artery elasticity index (SAEI) increased from 2.7+/-1.3 to 5.9+/-2.8 ml/mm Hg x 100 (p<0.0001). Systemic vascular resistance (SVR) decreased from 1881.5+/-527.5 to 1520.9+/-271.8 (p<0.0006). In patients treated with conventional doses of Candesartan: LAEI index increased from 11.0+/-3.5 to 14.4+/-3.2 ml/mm Hg x 100 (p<0.0001). SAEI increased during the study from 3.7+/-1.4 to 5.4+/-2.1 ml/mm Hg x 100 (p<0.0001). SVR decreased from 1699.8+/-327.6 to 1400.7+/-241 (p<0.0001). In the control group: neither LAE nor SAE improved during the treatment period. Although similar reduction in blood pressure was observed in all three groups, both LAE and SAE improved only in patients treated by ARBs. Treatment with high doses of Candesartan improves arterial stiffness to a greater extent than conventional doses of Candesartan, despite comparable changes in blood pressure.

Effect of long-term treatment with rosiglitazone on arterial elasticity and metabolic parameters in patients with Type 2 diabetes mellitus: a 2-year follow-up study.

AIMS: Thiazolidinediones may influence the atherogenic process by improving cardiovascular risk factors. The present study was designed to determine the long-term effect of rosiglitazone on arterial compliance and metabolic parameters in patients with Type 2 diabetes. METHODS: In an open-label, prospective study, 65 diabetic patients received rosiglitazone orally (4-8 mg/day) for 6 months. After 6 months, the patients continued an open follow-up study and were divided into two groups: group 1 included patients continuing rosiglitazone for 2 years, group 2 included patients discontinuing rosiglitazone and receiving other oral glucose-lowering agents. Lipid profile, glycated haemoglobin (HbA1c), insulin, C-peptide, fibrinogen, high-sensitivity-CRP and homeostasis model assessment-insulin resistance were measured. Arterial elasticity was assessed using pulse wave contour analysis. RESULTS: In patients treated with rosiglitazone for 2 years: the large artery elasticity index (LAEI) increased from 10.0 +/- 4.6 to 13.9 +/- 4.7 ml/mmHg x 100 after 2 years (P = 0.003). The small artery elasticity (SAEI) index increased significantly from 3.2 +/- 1.2 to 5.1 +/- 1.9 (P < 0.0001). In patients who discontinued rosiglitazone: LAEI did not change after 6 months, but decreased from 12.1 +/- 5.4 to 8.9 +/- 3.9 ml/mmHg x 10 (P < 0.0001) at the end of 2 years. SAEI increased during the first 6 months of treatment, from 3.9 +/- 1.8 to 5.1 +/- 1.5 ml/mmHg x 100 (P < 0.0001) and decreased after discontinuation of rosiglitazone (P = 0.042). CONCLUSIONS: Prolonged treatment with rosiglitazone improved arterial elasticity. However, significant deterioration in LAEI and SAEI was observed in patients who discontinued rosiglitazone. The beneficial vascular effect of rosiglitazone on arterial elasticity was independent of glycaemic control.

Long-term thyrotropin-suppressive therapy with levothyroxine impairs small and large artery elasticity and increases left ventricular mass in patients with thyroid carcinoma.

BACKGROUND: Exogenous subclinical hyperthyroidism, caused by long-term thyrotropin (TSH)-suppressive treatment with levothyroxine (LT(4)), is associated with several cardiovascular abnormalities. In order to assess the effect of long-term thyroid hormone-suppressive therapy on the blood vessels and myocardium, we determined the arterial elasticity, using the pulse wave contour analysis. METHODS AND RESULTS: Twenty-six athyreotic patients receiving TSH-suppressive LT(4) therapy for periods ranging from 3 to 21 years at a mean daily dose of 2.25 +/- 0.5 microg/kg per day were included in the study. Twenty six age- and gender-matched healthy subjects served as controls. Arterial elasticity of large and small arteries was evaluated using pulse wave contour analysis method (HDI CR 200, Eagen, MN). Cardiac structure was assessed by two-dimensional echocardiography. We found decreased large artery elasticity in subclinical hyperthyroidism (sHT) patients compared to controls (14.14 +/- 3.38 versus 10.53 +/- 2.43 L/mm Hg x 100, p < 0.000). Small artery elasticity was also lower in patients than in controls (5.42 +/- 1.82 versus 4.30 +/- 1.75 mL/mm Hg x 100, p < 0.056). The echocardiographic data showed significantly increased left ventricular (LV) mass index (101.90 +/- 18.61 versus 88.03 +/- 22.01 g/m(2), p < 0.049) and interventricular septum thickness (10.61 +/- 1.46 versus 9.11 +/- 1.13 mm, p < 0.002) in LT(4)-treated patients compared to controls. CONCLUSIONS: We found impaired vascular elasticity of large and small arteries and increased LV mass in patients receiving long-term TSH-suppressive therapy with LT(4).

The effect of a rapid weight loss induced by laparoscopic adjustable gastric banding on arterial stiffness, metabolic and inflammatory parameters in patients with morbid obesity.

OBJECTIVE: To determine the effect of drastic weight loss on arterial compliance, inflammatory and metabolic parameters in patients with morbid obesity with and without cardiovascular risk factors who underwent laparoscopic adjustable gastric banding (LAGB). DESIGN: Open prospective study, morbidly obese subjects divided into low- and high-risk group were evaluated before and 4 months after LAGB. SUBJECTS: Forty-one Caucasian subjects aged between 16 and 55 years, with morbid (grade 3) obesity (20 low- risk and 21 high-risk subjects) who underwent LAGB and completed a 16-week follow-up. MEASUREMENTS: Patients were evaluated at baseline and 4 months after LAGB for body mass index (BMI), arterial blood pressure (BP), metabolic factors including lipid profile, HbA1C, insulin, C-peptide, fibrinogen, hs-C reactive protein (CRP) and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity of large and small arteries was evaluated using pulse-wave contour analysis method (HDI CR 2000, Eagan, Minnesota) at baseline and after 4 months. RESULTS: Body mass index reduction induced by LABG, from 43.55+/-5.11 to 35.10+/-4.87 in low-risk patients and from 42.90+/-3.22 to 35.00+/-3.24 in high-risk patients, significantly improved small artery elasticity (SAE) from 6.30+/-2.74 to 7.25+/-1.85, in morbidly obese patients with multiple cardiovascular risk factors (high-risk group). Improvement in SAE was accompanied by improvement of arterial BP, glucose and lipid metabolism, and reduction of CRP values. CONCLUSION: Although dramatic weight reduction induced by surgical intervention was associated with similar changes in body weight and significant improvement of metabolic and inflammatory parameters in two groups of obese patients, SAE improved only in high-risk patients.

The Ashkelon Hypertension Detection and Control Program (AHDC Program): a community approach to reducing cardiovascular mortality.

BACKGROUND: Blood pressure (BP) reduction is crucial in reducing cardiovascular (CV) morbidity and mortality in the community. Subjects aged 20-65 seldom visit the primary care clinics, so they are unlikely to be detected without an active outreach screening program. The aim of the project was to prepare a professional doctor-nurse screening team, who will instruct those found to be at high risk in control of their risk factors, in order to reduce CV morbidity and mortality. METHODS: During a 10-year period (1980-1990), teams examined 12,202 subjects, (mean age 51 +/- 7 years, range 20-65 years) accounting for 23.4% of the total regional population. High risk subjects underwent an intensive CV risk factor control program. RESULTS: Subjects (3,506 or 28.6%) were found to have one or more CV risk factors (hypertension, obesity, smoking, hypercholesterolemia). During an average of 2 years, follow-up BP, weight reduction, and smoking cessation remained statistically significant. Total cholesterol was unchanged. Over this period, the standardized mortality ratio (SMR) in the area for acute MI fell from 100 to 76 (P < 0.01), for CV disease from 129 to 107 (P < 0.0001), and for hypertension from 121 to 87 (P < 0.1 NS). The project saved many life-years at no additional net cost to society, and cost effectiveness analysis showed positive results. CONCLUSIONS: A community approach with mainly nonpharmacological treatment is feasible and cost effective in reducing CV morbidity and mortality.

Risk factor profile and achievement of treatment goals among hypertensive patients from the Israeli Blood Pressure Control (IBPC) program--initial cost utility analysis.

AIMS: Blood pressure (BP) reduction is crucial in reducing cardiovascular morbidity and mortality. The IBPC (Israeli Blood Pressure Control) program was initiated in order to enhance the control of modifiable risk factors among high-risk hypertensive patients under follow-up by general practitioners in Israel. The cost effectiveness of an intervention program is an important factor in the decision-making process of its implementation and therefore was evaluated here. The objective of this evaluation is to estimate the costs, monetary savings and benefits in terms of QALYs (quality-adjusted life years) that would be expected if the program were to be expanded to 100 clinics nationwide, enabling around 14800 persons to be treated. METHODS: Hypertensive patients were screened in 30 general practice clinics, supervised by specialists in family medicine, each seeing 1000-5000 patients; 50-250 hypertensive patients were diagnosed at each participating clinic. BP levels, body mass index (BMI), lipid and glucose levels, as well as target organ damage and medications were recorded for all patients. RESULTS: A total of 4948 (2079, 42% males) were registered. Mean age was 64.8 +/- 12 years. After 1 year of follow-up versus baseline, the various parameters were as follows: BP control was achieved in 46.4% vs 29% of all hypertensive patients. LDL control (JNC VI criteria) was achieved in 41.7% vs 31.2% of all patients. Fasting plasma glucose control (glucose < 126 mg/dl) was achieved in 22% vs 19% of diabetic patients and 5.2% vs 3.1% of the diabetics had fasting plasma glucose levels > 200 mg/dl. Obesity (BMI > 30 kg/m2) was noted in 36.7% vs 43.8% at baseline. The cost utility analysis of the reduction in risk factors was calculated based on the international dicta applied to the reduction in risk factors as a result of treatment. For 100 clinics nationwide and 14800 persons to be treated the net saving to health services would be $977993 and the increase in QALYs would be 602 years. CONCLUSIONS: Better risk factor control in hypertensive patients by general practitioners could reduce morbidity and mortality as well as be cost effective.

Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia.

BACKGROUND: We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia. METHODS: Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks. RESULTS: After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6+/-0.5 to 5.6+/-0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively). CONCLUSIONS: We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.

[Atherosclerosis as an autoimmune disease].

The first medical conference on the subject of atherosclerosis and the immune system was held this year in Geneva Switzerland (8-11/3/2001) and included presentations by leading researchers in this field. Briefly, the discussions concluded that the immune system has a major role in the induction of atherosclerosis, at the beginning, and in the initiation of the atherosclerotic plaque rupture, in the end. Moreover, modifications in the inflammatory system have been shown (only in experimental models) to reduce the rate of the development of atherosclerosis. It might be assumed that some part of the role that statins in this event reduction can be attributed to the anti-inflammatory property of the drug. It is clear that better understanding of this issue will evolve, and in the future, new modalities of treatment will develop that will act by influencing the inflammatory system.

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations.

OBJECTIVES: This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and the effect of its correction on cardiac and renal function and hospitalization. BACKGROUND: The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown. METHODS: In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find the prevalence and severity of anemia (hemoglobin [Hb] <12 g). In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%. The doses of the CHF medications, except for diuretics, were not changed during the intervention period. RESULTS: The prevalence of anemia in the 142 patients increased with the severity of CHF, reaching 79.1% in those with New York Heart Association class IV. In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 +/- 5.5 months. The mean Hb level and mean left ventricular ejection fraction increased significantly. The mean number of hospitalizations fell by 91.9% compared with a similar period before the study. The New York Heart Association class fell significantly, as did the doses of oral and intravenous furosemide. The rate of fall of the glomerular filtration rate slowed with the treatment. CONCLUSIONS: Anemia is very common in CHF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.

Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety.

OBJECTIVE: To determine the efficacy and safety of a statin-fibrate combination in diabetes patients. DESIGN.: An open 21-month trial in which each patient first received the single drug for 6 months and then a combination of the two for 1 year. SETTING: Three lipid clinics in university-based tertiary care hospitals. PATIENTS: One hundred and forty-eight patients with type 2 (non-insulin-dependent, NIDDM) diabetes mellitus under stable control for 3 months by means of diet and oral hypoglycaemic medication. INTERVENTION: Patients from one clinic (n = 48) received bezafibrate slow release (400 mg day-1), and patients from the other two clinics (n = 100) received simvastatin 20 mg day-1. Six months later, all patients were switched to a daily combination of 400 mg bezafibrate slow release and 20 mg simvastatin for 1 year. RESULTS: The combination of statin and fibrate led to a 23% reduction in total cholesterol, 42% reduction in triglycerides, 29% reduction in LDL-c, 25% increase in HDL-c, 10% decrease in fibrinogen and 19% reduction of Lp(a) levels, and a decrease in the cholesterol/HDL-c ratio (from 8.9 to 5.4) in all 148 patients. Cardiovascular (CV) event rate was significantly reduced from 9.5% during the first 6 months of the study to less than 2% during the last year of the study (whilst on combination Rx). Side-effects with all treatments included only two patients who developed myopathy when on the combined regimen and one on the single statin regimen. However, plasma creatinine phosphokinase (CPK) levels doubled (but remained within the normal range) in most of the patients on combination therapy, compared with only a mild increase in patients receiving a single medication. CONCLUSIONS: The statin and fibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidaemia, as evidenced by improvement in the lipoprotein profile, reductions in Lp(a), fibrinogen and CV event rate, and almost no clinically significant side-effects.

Medical history of hypercholesterolaemia adversely affects the outcome of out-of-hospital cardiopulmonary resuscitation; the 'Shahal' experience in Israel.

AIMS: To evaluate the impact selected risk factors for cardiac death may have on the success rate in a large cohort of subscribers to 'SHAHAL' who were resuscitated from out-of-hospital cardiac arrest. METHODS AND RESULTS: In this medical facility currently serving 50 000 subscribers, data were prospectively gathered from between 1987-1998. The information retrieved from the patients' medical records included a medical history of hypertension, diabetes, hypercholesterolaemia (>220.mg. dl(-1)) smoking, angina, previous myocardial infarction, and congestive heart failure. A total of 998 patients aged 74+/-12 years (mean+/-1 SD) were included. Death was announced at the scene for 659 (66%) victims, while 339 (34%) patients were taken to hospital. Of these 140 (14% of the total cohort) survived and were discharged from the hospital. A comparison of various selected parameters between survivors and non-survivors of resuscitation revealed that survivors were younger, had a higher rate of pulseless ventricular tachycardia/ventricular fibrillation, more were among the arrests witnessed by the 'SHAHAL' team, and that more had a shorter time lag to initiation of cardiopulmonary resuscitation than non-survivors. None of the studied risk factors predicted the outcome of cardiopulmonary resuscitation, with the exception of hypercholesterolaemia, which carried a significantly worse prognosis for cardiopulmonary resuscitation (P=0.009). CONCLUSIONS: A medical history of hypercholesterolaemia appears to be an important risk factor which adversely affects the outcome of cardiopulmonary resuscitation.

Diurnal heterogeneity in structure and function of low density lipoproteins of normolipidemic males.

Structural changes in low density lipoproteins (LDL) have been shown to alter their metabolism and atherogenic potential. We investigated the diurnal changes in size and composition of LDL in seven healthy, non-obese, normolipidemic male volunteers consuming a standard diet (14.5% protein, 31.9% fat, 53.6% carbohydrate and 383 mg cholesterol/day) and continuing their daily routine. The food was divided into three meals and three snacks, and blood samples were obtained at 7 AM (after 12 h fasting), noon, 8 PM, midnight and 3 AM. LDL were isolated by both sequential and density gradient ultracentrifugation (d = 1.019 - 1.050 g/ml), and analyzed for lipids, apolipoproteins, size, and affinity to LDL receptors. Diurnal LDL preparations differ from fasting LDL in both chemical and physical parameters. The former get richer in triglyceride (TG/cholesterol weight ratio 0.23 vs. 0.16), larger in diameter (21.2 +/- 0.2 vs. 22.4 +/- 0.1 nm), and enriched in a more buoyant fraction (74.0 +/- 4.6 vs. 41.9 +/- 3.8% of LDL cholesterol in d = 1.019 - 1.035 g/ml). These structural changes in LDL were associated with enhanced affinity to LDL receptors in both human skin fibroblasts and HepG2 cells, as demonstrated by competition experiments with fasting human 125I-LDL. The observed diurnal heterogeneity in both the structure and the function of LDL may be attributed to the absorptive state as it did not occur during prolonged fasting. These diurnal changes may be important for better understanding LDL metabolism in vivo and for the elucidation of the atherogenic process.