Ardon Rubinstein

Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years

Abstract Objective: To test the hypothesis that subjects who clear chylomicron remnants slowly from plasma may be at higher risk of coronary artery disease than indicated by their fasting plasma lipid concentrations. Design: Case control study over three years. Setting: An 800 bed general municipal hospital. Subjects: 85 normolipidaemic patients with coronary artery disease selected prospectively and matched with 85 normolipidaemic subjects with normal coronary arteries on angiography. Interventions: All subjects were given a vitamin A fat loading test which specifically labels intestinal lipoproteins with retinyl palmitate. Main outcome measure: Postprandial lipoprotein metabolism. Results: The area below the chylomicron remnant retinyl palmitate curve was significantly increased in the coronary artery disease group as compared with the controls (mean 23.4 (SD 15.0) v 15.3 (8.9) µmol/l.h; 95% confidence interval of difference 4.37 to 11.82). Conclusions: Normolipidaemic patients with coronary artery disease had significantly higher concentrations of chylomicron remnants in plasma than normolipidaemic subjects with normal coronary vessels. This may explain the mechanism underlying the susceptibility to atherosclerosis of coronary artery disease patients with normal fasting lipid values. As diet and drugs can ameliorate the accumulation of postprandial lipoproteins in plasma, the concentration of chylomicron remnants should be measured in patients at high risk of coronary artery disease. Key messages Key messages The atherogenic effect of postprandial lipoproteins is hypothesised to be inversely related to their metabolic capacity Patients with coronary artery disease have decreased metabolic capacity of chylomicron remnants as compared with subjects with normal coronary arteries An ensuing postprandial dyslipidaemia may exist in patients with coronary artery disease who have normal fasting lipid values A vitamin A fat loading test may be useful in identifying these patients

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

Abstract. Gavish D, Leibovitz E, Shapira I, Rubinstein A (Wolfson Medical Center, Holon, and Tel Aviv Sourasky Medical Center, Tel Aviv, Israel). Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. J Intern Med 2000; 247: 563–569.

Increased retinal blood flow velocity in patients with early diabetes mellitus.

Purpose: To compare retinal blood flow velocity in small vessels of patients with early diabetes mellitus (DM), without any morphologic changes related to diabetic retinopathy, with that in a control group. Methods: The authors used the retinal function imager to measure blood flow velocities, from many small vessels, simultaneously. Twenty-three eyes of 14 patients with early DM and 51 eyes of 31 healthy subjects were enrolled. Differences between the patients and the control group were assessed by mixed linear models. Results: Venous average velocity significantly increased in the DM group (3.8 ± 1.2 vs. 2.9 ± 0.5 mm/second, P < 0.0001) than in the healthy subjects. Arterial velocity of DM patients was also significantly higher (4.7 ± 1.7 vs. 4.1 ± 0.9 mm/second, P = 0.03). There was no statistically significant difference between groups in age, gender, heart rate, and systolic blood pressure. The diastolic blood pressure in the DM patients was lower than that in the healthy group (P = 0.03). Conclusion: There was an increase in arterial and venous retinal blood flow velocities of patients with early DM with no diabetic retinopathy. These findings support the notion that abnormalities in vessel function exist in diabetic eyes before the development of structural changes. This noninvasive approach facilitated the assessment of early hemodynamic abnormalities and may assist in screening and monitoring.

Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice

AIM Clopidogrel is a widely used anti-thrombotic for the prevention of stent thrombosis and cardiovascular events in patients with coronary atherosclerosis. Clopidogrel has been shown to exhibit anti-inflammatory effects that are related to the attenuated activation of platelets. Atherosclerosis is a complex process in which the immune system and the endothelium appear to play a prominent role. Herein, we tested the hypothesis that clopidogrel will influence plaque size and composition in the atherosclerosis prone apolipoprotein E knockout (apoE KO) mouse model. METHODS AND RESULTS Eight week old mice were fed daily with either PBS, 1 mg or 2 mg of clopidogrel for 10 weeks. Plaque size was evaluated in the aortic sinus and cellular and humoral responses were studied as well as splenic and bone marrow endothelial progenitors by FACS. Treatment with either 1 mg and 2 mg of clopidogrel significantly reduced plaque size and augmented its stability by increasing atheromatous fibrous area. Whereas antigen specific oxLDL immune response was not influenced by clopidogrel feeding, the number of atheroprotective regulatory CD4+CD25+ T cells was significantly increased. Moreover, clopidogrel treatment resulted in a prominent rise in splenic but not bone marrow derived Sca-1+/flk-1+ endothelial progenitors. CONCLUSION Clopidogrel significantly reduces atheroma burden and stabilizes aortic sinus plaques in apoE KO mice. These effects may partially be mediated by upregulation of the regulatory T cell pool and splenic endothelial progenitor cells. These findings may expand the potential applications of clopidogrel in human subjects.

The erythrocyte adhesiveness/aggregation test (EAAT): A new biomarker to reveal the presence of low grade subclinical smoldering inflammation in individuals with atherosclerotic risk factors

BACKGROUND Multiple acute phase proteins and atherosclerotic risk factors increase the aggregability of erythrocytes. METHODS AND RESULTS We used a simple slide test and image analysis to determine the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of 222 women and 221 men with no, one, two or more atherosclerotic risk factors. The degree of erythrocyte adhesiveness/aggregation correlated significantly with the concentration of commonly used variables of the acute phase response. We also showed that individuals with low erythrocyte adhesiveness/aggregation tend to be younger and to have fewer risk factors for atherosclerosis, including diabetes mellitus, hypertension, hyperlipidemia and smoking. CONCLUSIONS The association between increased erythrocyte adhesiveness/aggregation, higher concentrations of acute phase proteins, and increased atherosclerotic risk factors points to a possible clinical applicability of the erythrocyte adhesiveness/aggregation test (EAAT) to reveal the presence of both low-grade subclinical smoldering inflammation and morbid biology in individuals with risk factors for atherosclerosis.

HIF-1α Overexpression and Experimental Murine Atherosclerosis

Background—Lymphocytes play an important role in the progression of atherosclerosis. Recently, hypoxia inducible factor-1 (HIF-1) was found to attenuate inflammation by regulating T cell activation and cytokine production. We studied the effects of overexpression of HIF-1&agr; in ApoE knockout murine lymphocytes, on experimental atherosclerosis. Methods and Results—ApoE−/− mice were submitted to intravenous hydrodynamic injection of empty plasmid or HIF-1&agr;P564A (HIF-1&agr; mutated stabilized construct). Robust expression of HIF-1&agr; was evident in spleen cells of recipient animals. Increased expression of IL-10 as well as decreased expression of IFN-&ggr; was measured in splenocytes of HIF-1&agr;-treated mice by RT-PCR. One week postinjection, antibody array analysis revealed a pattern consistent with a T helper 1 to T helper 2 shift. On sacrifice, assessment of aortic sinus lesions revealed a significant reduction in plaque size in HIF-1&agr; injected mice. A reduced expression of IFN-&ggr; was evident in CD4+ spleen-derived lymphocytes and aortas of HIF-1&agr;-injected mice. Conclusions—HIF-1&agr; expression in mouse lymphocytes is associated with a reduced IFN-&ggr; expression and attenuation of experimental atherosclerosis.

Serum lipids and lipoprotein concentrations during the acute phase of myocardial infarction.

The concentrations of serum lipids and lipoprotein cholesterol were measured serially during the acute phase (14 days) following myocardial infarction (MI) in 13 male survivors. All patients were re-examined at least two months after discharge from hospital. A significant increase in serum triglyceride (TG) concentration occurred during the acute phase, with values returning to baseline two months after recovery. No changes in the concentrations of the other lipids or lipoprotein cholesterol were observed.

Hormone replacement therapy enhances postprandial lipid metabolism in postmenopausal women

Postmenopausal estrogen therapy reduces cardiovascular morbidity and mortality, except in women with advanced coronary disease. This beneficial effect is partly attributed to a reduction of fasting plasma total and low-density lipoprotein cholesterol (LDL-C) and an elevation of plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Since postprandial lipemia seems to play a role in the pathogenesis of coronary artery disease, we evaluated the effect of hormone replacement therapy (HRT) on postprandial lipoprotein metabolism in 14 normolipemic postmenopausal women. A vitamin A fat-loading test before and after three cycles of treatment with a sequential combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) was used to label chylomicrons and chylomicron remnants with retinyl palmitate (RP), and RP clearance was assessed over an 8-hour period postprandially. Following 3 months of HRT, fasting total cholesterol and LDL-C levels were reduced 9.8% (P = .049) and 16.5% (P = .023), respectively. Fasting HDL-C levels increased 18.9% (P = .001). Fasting triglycerides (TGs) increased, but not significantly. Postprandial integrated plasma TGs did not change significantly. The integrated RP levels in whole plasma and chylomicron (Svedberg flotation units [Sf] > 1,000) and nonchylomicron (Sf < 1,000) fractions were reduced 58% (P = .043), 78% (P = .041), and 75% (P = .001), respectively, after hormonal treatment. Enhanced clearance of chylomicrons and chylomicron remnants by HRT may contribute to the protective effect of estrogens against cardiovascular disease in normolipemic postmenopausal women.

Serum lipids and lipoprotein concentrations in young quadriplegic patients

Serum lipids and lipoproteins were investigated in 10 young quadriplegic patients. All received intermittently a liquid formula diet via a naso-gastric tube, consisting of 2900 calories/day. The polyunsaturated/saturated fatty acids ratio was 1.1 : 1. Their mean body weight was 70% of the ideal body weight. The results were compared to a control group receiving a diet containing 2600 calories per day, and the polyunsaturated/saturated fatty acids ratio was 0.9 : 1. Their mean body weight was 95% of the ideal body weight. In the quadriplegic group the serum HDL-cholesterol levels and linoleic acid content of cholesterol ester were reduced. Similar findings have been observed in patients with coronary disease.

Baseline Low-Density Lipoprotein Cholesterol Levels and Outcome in Patients With Heart Failure

The incidence of heart failure (HF) is constantly increasing in the Western world. Treatment with statins is well established for the primary and secondary prevention of cardiac events by lowering low-density lipoprotein (LDL) cholesterol levels. There are conflicting reports on the role of LDL cholesterol as an adverse prognostic predictor in patients with advanced HF. The aim of this study was to investigate the association between LDL cholesterol levels and clinical outcomes in 297 patients with severe HF (average New York Heart Association class 2.8). The mean follow-up period was 3.7 years (range 8 months to 11.5 years), and 37% of the patients died during follow-up. The mean time to first hospital admission for HF was 25 +/- 17 months. The study group was divided according to plasma LDL level < or =89, >89 to < or =115, >115 mg/dl. Patients with the highest baseline LDL cholesterol levels had significantly improved outcomes, whereas those with the lowest LDL cholesterol levels had the highest mortality. When analyzed with respect to statin use, it emerged that the negative association between LDL cholesterol level and mortality was present only in the patients with HF who were treated with statins. In conclusion, lower LDL cholesterol levels appear to predict less favorable outcomes in patients with HF, particularly those taking statins, raising questions about the need for aggressive LDL cholesterol-lowering strategy in patients with HF, regardless of its cause.