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Dive into the research topics where Rafael Bitzur is active.

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Featured researches published by Rafael Bitzur.


Diabetes Care | 2008

Changes in Triglyceride Levels Over Time and Risk of Type 2 Diabetes in Young Men

Amir Tirosh; Iris Shai; Rafael Bitzur; Ilan Kochba; Dorit Tekes-Manova; Eran Israeli; Tzippora Shochat; Assaf Rudich

OBJECTIVE—The association between changes in triglyceride concentrations over time and diabetes is unknown. We assessed whether two triglyceride determinations obtained 5 years apart can predict incident type 2 diabetes. RESEARCH DESIGN AND METHODS—Triglyceride levels at baseline (time 1) and 5 years later (time 2), followed by subsequent follow-up of 5.5 years, were measured in 13,953 apparently healthy men (age 26–45 years) with triglycerides <300 mg/dl (<3.39 mmol/l). RESULTS—During 76,742 person-years, 322 cases of diabetes occurred. A multivariate model adjusted for age, BMI, total cholesterol–to–HDL cholesterol ratio, family history of diabetes, fasting glucose, blood pressure, physical activity, and smoking status revealed a continuous independent rise in incident diabetes with increasing time 1 triglyceride levels (Ptrend < 0.001). Men in the lowest tertile of time 1 triglyceride levels who progressed to the highest tertile over follow-up (low-high) exhibited a hazard ratio (HR) of 12.62 (95% CI 3.52–31.34) compared with those remaining in the lowest tertile at both time points (reference group: low-low). Whereas men who were at the top triglyceride level tertile throughout follow-up (high-high) had a HR for diabetes of 7.08 (2.52–14.45), those whose triglyceride level decreased to the lowest tertile (high-low) exhibited a HR of 1.97 (0.67–6.13). Alterations in triglyceride levels during follow-up were associated with changes in BMI, physical activity, and eating breakfast habit (P < 0.05), but remained an independent modifier of diabetes risk even after adjustment for such changes. CONCLUSIONS—Two measurements of fasting triglyceride levels obtained 5 years apart can assist in identifying apparently healthy young men at increased risk for diabetes, independent of traditional risk factors and of associated changes in BMI and lifestyle parameters.


Diabetes Care | 2009

Triglycerides and HDL cholesterol: stars or second leads in diabetes?

Rafael Bitzur; Hofit Cohen; Yehuda Kamari; Aviv Shaish; Dror Harats

Diabetes carries a high risk of atherosclerosis, and cardiovascular disease, especially coronary heart disease (CHD) and stroke, is by far the leading cause of death among patients with type 2 diabetes. Although statins reduce the risk of major vascular events by about one-fifth per millimole per liter reduction in LDL cholesterol, with similar proportional reductions in major coronary events, stroke, and the need for coronary revascularization, the residual risk remains high. In the Scandinavian Simvastatin Survival Study (4S) (1), although the relative risk reduction in diabetic patients was larger than in nondiabetic patients, simvastatin-treated diabetic patients were still at higher risk of death than the placebo-treated nondiabetic patients. Multifactorial intervention reduces the risk even further, but significant danger remains. Current guidelines call for an aggressive treatment strategy to reduce LDL cholesterol, blood pressure, and glucose levels in diabetic patients, but data concerning the management of high triglyceride (TG) levels and low HDL cholesterol levels remains inconclusive. This article reviews the data concerning diabetic dyslipidemia and its management. The cluster of lipid abnormalities associated with type 2 diabetes is defined by a high concentration of TG and small dense LDL and a low concentration of HDL cholesterol. Plasma LDL cholesterol levels are generally normal. Insulin resistance is believed to contribute to this atherogenic dyslipidemia by increasing the hepatic secretion of VLDL and other apolipoprotein (apo)B-containing lipoprotein particles, as a result of increased free fatty acid flux to the liver (2,3). This may also be the result of a diminished suppressive effect of insulin on apoB secretion, either at the level of the regulation of apoB degradation, or inhibition of microsomal TG transfer protein activity (4). Through the action of cholesterol ester transfer protein, TGs are transferred from VLDL to HDL, creating TG-rich HDL particles, which are hydrolyzed by hepatic …


Diabetes Care | 2013

Intolerance to Statins: Mechanisms and Management

Rafael Bitzur; Hofit Cohen; Yehuda Kamari; Dror Harats

Statins are considered very effective in reducing cardiovascular morbidity and mortality in high-risk patients. However, although adherence to statins improves morbidity and mortality (1), it remains suboptimal (2). One of the most important causes of nonadherence is the so-called statin intolerance, mainly because of muscle-related symptoms. These symptoms most often consist of myalgia unaccompanied by significant creatine kinase (CK) elevations. Less often, myositis (elevated CK >10 times the upper limit of normal) or rhabdomyolysis (CK level >10,000 IU/L or accompanied by significant elevation in creatinine level) develops. In randomized controlled trials, the incidence of statin myopathy is ~1.5–5.0% (3). However, this low incidence may be misleading for several reasons. First, in most studies patients with a history of statin intolerance were excluded. Other studies had a single-blinded statin run-in phase, and patients experiencing muscle-related symptoms or CK elevations during this phase were excluded. Patients who tend to be at risk for developing muscle-related symptoms, such as women, elderly patients, and patients with significant comorbidity, who comprise a large proportion of statin-treated patients in real-life settings, are underrepresented in randomized controlled trials. Some studies have defined muscle-related effects by elevated CK levels only, disregarding myalgia. Last but not least, patients enrolled in studies might be motivated and so minimize reporting of mild myalgias, thus leading to underestimation of the magnitude of the problem. Data concerning real-life incidence of statin-related myopathy are scarce. In the Prediction of Muscular Risk in Observational Conditions (PRIMO) study (4), 7,924 patients receiving high-dosage statin therapy in an outpatient setting in France were asked about muscle-related symptoms. Overall, muscular symptoms were reported by 10.5% of the patients. A weakness of this study is that it lacked a comparison/control group not treated with statins. In a study of adults aged ≥40 years who participated in National Health and …


Pathobiology | 2000

Suppression of atherogenesis in female low-density lipoprotein receptor knockout mice following magnesium fortification of drinking water: the importance of diet.

Yaniv Sherer; Yehuda Shoenfeld; Aviv Shaish; Hana Levkovitz; Rafael Bitzur; Dror Harats

Objective: Magnesium (Mg) has previously been found to modulate blood lipid levels, atherogenesis and atherosclerosis in rabbits when used as a dietary supplement. In addition, we have reported that Mg fortification of drinking water can attenuate atherogenesis in male low-density lipoprotein (LDL)-receptor-deficient mice, but had a mild and nonsignificant effect on female mice fed a high-cholesterol diet supplemented with cholic acid. The aim of this study was to examine whether Mg has an antiatherogenic effect in female mice fed a high-cholesterol diet without cholic acid. Methods: Two groups of female LDL-receptor-deficient mice were included. The mice received either distilled water or water with 50 g of Mg sulfate per liter. In the first (12 weeks) and second (6 weeks) stages of the experiment, the mice received low- and high-cholesterol diets, respectively, both without cholic acid. At the end of each stage of the experiment, blood was drawn for the determination of plasma Mg, calcium and lipid levels. In addition, the extent of atherosclerosis was determined at the aortic sinus level. Results: Mg fortification was associated with higher levels of plasma Mg while the mice were on a high-cholesterol diet, and the extent of atherosclerosis at the aortic sinus was significantly decreased in the female mice that received high levels of Mg compared with the female mice that received distilled water. The female mice that received water fortified with Mg had lower levels of triglycerides after stage 2, whereas no differences regarding cholesterol levels were found. Conclusion: These results confirm that Mg fortification of drinking water is capable of inhibiting atherogenesis also in female LDL-receptor-deficient mice fed a high-cholesterol diet, and demonstrate the importance of the nutritional composition of diet in this experimental model.


Diabetes Care | 2009

Should All Diabetic Patients Be Treated With a Statin

Yehuda Kamari; Rafael Bitzur; Hofit Cohen; Aviv Shaish; Dror Harats

The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% (171 million) in the year 2000, and the projected number could rise to 4.4% (366 million) in 2030 (1). This rapid rise is mainly attributable to the increase of diabetes. The continuing escalation of obesity and the metabolic syndrome contribute to the upsurge in frequency of diabetes (2,3). Interestingly, the appreciation in the number of people >65 years of age was found to be the most important demographic change to diabetes prevalence around the world, indicating that the “diabetes epidemic” will continue even if levels of obesity remain constant. Therefore, it is likely that future diabetes preponderance is underestimated, given the growing frequency of obesity (1). Because the vast majority of diabetic patients have type 2 diabetes and almost all the studies were performed in such subjects, in this article, “type 2 diabetes” will be referred to as “diabetes.” Cardiovascular disease (CVD) is one of the foremost causes of mortality and is a major contributor to morbidity for individuals with diabetes. In addition, diabetes is an independent risk factor for macrovascular disease, as are the common coexisting conditions (hypertension and dyslipidemia). The U.K. Prospective Diabetes Study (UKPDS) evaluated baseline risk factors for coronary artery disease in patients with newly diagnosed diabetes without evidence of vascular disease. When comparing the relative contribution of the three modifiable coexisting conditions (dyslipidemia, hypertension, and hyperglycemia) with development of future coronary heart disease (CHD), the estimated hazard ratio (HR) for the upper third, relative to the lower third, for LDL cholesterol, systolic blood pressure, and A1C were 2.26, 1.82, and 1.52, respectively (4). This finding supports the notion that dyslipidemia, and specifically LDL cholesterol, are major contributors to the increased CHD risk in patients with diabetes (4,5 …


BioMed Research International | 2015

Vitamin A-Deficient Diet Accelerated Atherogenesis in Apolipoprotein E−/− Mice and Dietary β-Carotene Prevents This Consequence

Noa Zolberg Relevy; Dror Harats; Ayelet Harari; Ami Ben-Amotz; Rafael Bitzur; Ralph Rühl; Aviv Shaish

Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE−/−). ApoE−/− mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing βc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary βc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary βc, as a sole source of retinoids, can compensate for vitamin A deficiency.


Diabetes Care | 2016

Remembering Statins: Do Statins Have Adverse Cognitive Effects?

Rafael Bitzur

The issue of statin-associated cognitive impairment has been a hot topic among both patients and health care providers, especially since the U.S. Food and Drug Administration (FDA) issued a statement regarding rare postmarketing reports of ill-defined cognitive impairment associated with statin use. This statement was based on case reports, and no objective measures of cognitive function were used. Nevertheless, many patients at high risk of cardiovascular disease have expressed concerns about possible cognitive decline and may have opted to forgo statin therapy. In this overview, the evidence leading to the statement by the FDA is reviewed. Potential mechanisms of the effect of LDL cholesterol reduction and statin therapy on cognition are discussed. Evidence from observational and prospective randomized trials is summarized, leading to the conclusion that as for now, there is no good evidence that statins cause cognitive impairment to a significant degree. Reported cases seem to be rare, and a causal relationship has not been established.


Diabetes and Vascular Disease Research | 2008

Characterisation of atherosclerotic lesions with scanning electron microscopy (SEM) of wet tissue

Yehuda Kamari; Hofit Cohen; Aviv Shaish; Rafael Bitzur; Arnon Afek; Shlomzion Shen; Anya Vainshtein; Dror Harats

Atherosclerotic cardiovascular disease (CVD) is the universal leading cause of mortality and a major cause of morbidity. Additionally, the global epidemic of diabetes is associated with considerable cardiovascular mortality risk due to accelerated premature atherosclerosis. Development of effective therapies for atherosclerosis is dependent upon improved tools to assess atherosclerotic lesion progression in animal models. We present a novel technique that utilises scanning electron microscopy (SEM) for imaging wet biological specimens, thus enabling rapid and high-resolution imaging of atherosclerotic lesions. This wet SEM technique was used in an apoE-deficient mice model for morphological characterisation of early and advanced atherosclerotic lesions. Further demonstration of lipid-rich atherosclerotic lesions was carried out with osmium tetroxide staining for cholesterol. Gold immunolabelling of specific epitopes was applied in identification of the cellular and molecular components within the atherosclerotic lesions, namely foam cells, smooth muscle cells and collagen. The wet SEM technique demonstrates an accurate and detailed structural evaluation of the pathological process of atherosclerosis. Understanding the mechanisms that precipitate the atherosclerotic process, utilising this novel technique, may assist in the development of innovative therapeutic interventions for CVD management and prevention in the general population and in those with diabetes.


Diabetes Care | 2011

Diabetes and Cardiovascular Disease: When it comes to lipids, statins are all you need

Rafael Bitzur

The prevalence of obesity and diabetes continues to increase rapidly in the U.S. and all over the world (1–3). Obesity and diabetes are major risk factors for cardiovascular diseases (CVDs), but despite the increase in their prevalence, there seems to be a continuous steady decline in death rates from coronary heart disease (CHD) and stroke (4). Moreover, cause-specific excess death associated with obesity has been declining despite the increase in obesity rates (5). The reason behind this apparent paradox is probably a better control of other risk factors for CVD, such as cholesterol levels, hypertension, and smoking. Several trials demonstrated that more than half the decline in deaths from CHD in the last decades may be attributable to reductions in major risk factors (6). Of all risk factors, treating high cholesterol levels had the highest impact on the decline in CHD mortality (7). This is hardly surprising because the LDL cholesterol level is the strongest determinant of CHD risk, even in diabetic patients (8). ### Prevention of CHD in diabetic patients and the question of residual risk Statins are the most effective agents in reducing the risk of CHD in diabetic patients, reducing the relative risk by about one-third (9,10). An analysis based on the UK Prospective Diabetes Study (UKPDS) risk engine demonstrated that even in the Steno-2 study, in which multifactorial intervention was used for the treatment of diabetes with an impressive reduction of both cardiovascular morbidity and mortality, lipid-lowering therapy accounted for more than 70% of CVD risk reduction (11). Actually, many more patients in the intensive therapy group achieved their cholesterol goal compared with the conventional therapy group (70 vs. 20%), while there was no difference between the groups in the attainment of their triglyceride goal (11). The main difference between the intensive and conventional treatment groups was in the use of statins (12 …


Pathobiology | 2000

The Effect of Renin-Angiotensin Axis Inhibition on Early Atherogenesis in LDL-Receptor-Deficient Mice

Yehonatan Sharabi; Ehud Grossman; Yaniv Sherer; Aviv Shaish; H. Levkovitz; Rafael Bitzur; Dror Harats

Objective: The renin-angiotensin system may play a role in the development of atherosclerosis. Nevertheless, different results from studies attempting to attenuate the process by inhibiting the converting enzyme were equivocal, and in those who succeeded, blood pressure was lowered and/or the lipid profile was improved in addition to the inhibition of the renin-angiotensin axis. The aim of this study is to investigate the effect of low doses of fosinopril, a converting enzyme inhibitor, on the development of atherosclerosis in LDL-receptor-deficient mice. Methods: Three groups of 15 mice were fed a high-fat, high-cholesterol western diet. The three study groups received either distilled water (control group), or water supplemented with fosinopril 0.01 mg/kg/day (low-dose group) or with 0.1 mg/kg/day (high-dose group). Plasma aldosterone levels and lipid profiles were measured at the beginning and at the end of the study. After 10 weeks, the mice were sacrificed and the extent of atherosclerosis was assessed at the aortic sinus. Results: Plasma aldosterone levels did not change in the control group, but decreased significantly in both treated groups from 74.7 to 39.3 ng/ml in the low-dose group (p < 0.003) and from 70.7 to 33.6 ng/ml in the high-dose group (p < 0.001). The lipid profile at the end of the study showed significantly lower levels of cholesterol and triglycerides in the high-dose group as compared to the low-dose group (p < 0.05). There was no difference between the three groups regarding the area of atherosclerosis at the aortic sinus: 157,000 ± 34,000, 130,000 ± 58,000 and 145,000 ± 26,000 µm2 in the control, low-dose and high-dose groups, respectively. Conclusion: Inhibition of the renin-angiotensin-aldosterone axis by itself does not prevent the development of early atherosclerosis in LDL-receptor-deficient mice.

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Ardon Rubinstein

Tel Aviv Sourasky Medical Center

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Dov Gavish

Wolfson Medical Center

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