Israel Medical Association Journal

Background: Increased levels of high density lipoprotein (over 60 mg/dl) are considered to be a risk factor for ischemic heart disease. However, some patients with high HDL[1] still develop cardiovascular diseases.

Objective: To find out why patients with very high HDL still suffer from cardiovascular diseases.

Methods: We analyzed several risk factors, such as increased lipid peroxidation, hyperhomeocysteinemia and increased release of inflammatory molecules that could be related to the development of vascular disease in patients with high serum HDL levels. Patients with HDL cholesterol levels above 75 mg/dl were selected for this study and were separated into two groups based on the presence of atherosclerotic vascular disease, i.e., those with vascular disease (patients) and those without (controls).

Results: Plasma isolated from the patient group exhibited significantly increased lipid peroxidation by 21% and decreased total antioxidant status by 17%, but there were no differences regarding their serum or their paraoxonase activity. Moreover, both groups exhibited similar levels of serum C-reactive protein, fibrinogen and homocysteine, enabling us to eliminate these risk factors in the etiology of cardiovascular disease in the patient group.

Conclusion: Increased oxidative stress could be one of the factors leading to cardiovascular diseases in patients with high serum HDL levels.

Background: The osteoporosis-pseudoglioma syndrome is a rare autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or early-onset blindness. Other manifestations include muscular hypotonia, ligamentous laxity, mild mental retardation and seizures. The gene responsible was recently identified to be the low density lipoprotein receptor-related family member LRP5 on chromosome 11q11-12.

Objective: To measure bone density in two siblings with the OPPG[1] syndrome as well as in their family members (parents and siblings).

Methods: Bone mineral density was determined in the lumbar spine (antero-posterior), femoral neck, two-thirds distal forearm (>95% cortical bone) and ultradistal forearm (predominantly trabecular bone) by dual-energy X-ray absorptiometry.

Results: The studies revealed osteoporotic changes both in the patients and the carriers.

Conclusion: The findings demonstrate that OPPG carriers have reduced bone mass, which is a risk factor for development of early osteoporotic changes.

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Background: Low density lipoprotein apheresis is used as a complementary method for treating hypercholesterolemic patients who cannot reach target LDL[1]-cholesterol levels on conventional dietary and drug treatment. The DALI system (direct absorption of lipoproteins) is the only extracorporeal LDL-removing system compatible with whole blood.

Objective: To describe our one year experience using the DALI[2] system.

Methods: LDL apheresis was used in 13 patients due to inability to reach target LDL-C levels on conventional treatment. They included seven patients with familial hypercholesterolemia, three who had adverse reactions to statins, and three patients with ischemic heart disease who did not reach LDL-C target level on medical treatment.

Results: The average triglyceride, total cholesterol, high density lipoprotein-C and LDL-C levels before and after treatment in all patients were: 170 ± 113 vs. 124 ± 91, 269 ± 74 vs. 132 ± 48, 42 ± 8 vs. 37 ± 7.9, and 196 ± 77 vs. 80 ± 52 mg/dl, respectively. Comparing the results of a subgroup of seven patients who had previously been treated with plasma exchange, it is noteworthy that while the reduction in triglyceride, total cholesterol and LDL-C are comparable, the effect on HDL[3]-C concentration was less apparent: from an average of 39.7 ± 8.7 and 23 ± 5.7 mg/dl before and after plasma exchange to an average of 43.9 ± 8.1 and 38.4 ± 7 mg/dl before and after LDL apheresis, respectively. Five patients developed treatment-related adverse events: three experienced allergic reactions manifested as shortness of breath, urticaria and facial flushing; one patient developed rhabdomyolysis, an adverse reaction that was not reported previously as a result of LDL apheresis; and one patient had myopathy with back pain. All untoward effects occurred during the first few treatment sessions.

Conclusions: LDL apheresis using the DALI system is highly efficacious for the treatment of hypercholesterolemia. It is associated with a significant number of side effects occurring during the first treatment sessions. In patients not experiencing adverse effects in the early treatment period, it is well tolerated, and can provide remarkable clinical benefit even after short-term therapy.

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Background: Hyperlipidemia is a major risk factor for coronary heart disease. Reducing low density lipoprotein-cholesterol can significantly reduce the risk of CHD[1], but many patients fail to reach the target LDL-C[2] goals due to low doses of statins or low compliance.

Objectives: To treat high risk patients with atorvastatin in order to reach LDL-C goals (either primary or secondary prevention) of the Israel Atherosclerosis Society.

Methods: In this open-label study of 3,276 patients (1,698 of whom were males, 52%), atorvastatin 10 mg was given as a first dose, with follow-up and adjustment of the dose every 6 weeks. While 1,670 patients did not receive prior hypolipidemic treatment, 1,606 were treated with other statins, fibrates or the combination of both.

Results: After 6 weeks of treatment, 70% of the patients who did not receive prior hypolipidemic medications and who needed primary prevention reached target LDL-C levels. Interestingly, a similar number of patients on prior hypolipidemic treatment reached the LDL-C goals for primary prevention. The patients treated with other statins, fibrates or both did not reach the LDL-C treatment goals. Only 34% of all patients who needed secondary prevention reached the ISA[3] LDL-C target of 100 mg/dl. Atorvastatin proved to be completely safe; only two patients had creatine kinase elevation above 500 U/L, and another six had mild CK[4] elevation (<500 U/L). None of the patients had clinical myopathy, and only one had to be withdrawn from the study.

Conclusion: Atorvastatin is a safe and effective drug that enables most patients requiring primary prevention to reach LDL-C goal levels, even with a low dose of 10 mg. Patients in need of secondary prevention usually require higher doses of statins.

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Background: Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes were proposed to be involved in osteoporosis, but the precise genes and their relative contribution remain unknown.

Objectives: To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986s in the calcium-sensing receptor gene.

Methods: We analyzed 86 Jewish Israeli patients with LBMD[1]: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR[2] gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986s polymorphism in the CaSR[3] gene was performed using the denaturing gradient gel electrophoresis technique.  

Reaults: In LBMD women the distributions of VDR alleres in Apal polymorphism were AA=7/28, Aa=16/28 and aa=5/28; in TaqI polymorphism TT=10/31, Tt=16/31 and tt=5/31; and in BsmI polymorphism BB=7/32, Bb=14/32 and 11/32. In LBMD men the distributions were AA=17/39, Aa=21/39 and aa=1/39; in TaqI polymorphism TT=12/42, Tt=23/42 and tt=7/42; and in BsmI polymorphism BB=12/41 Bb=18/41 and bb=11/41. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986s polymorphism, compared with 40 of 203 controls (19.7%) (P=0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD[4] between homozygotes and heterozygotes (P=0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.

Conclusions: In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.

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Background: Information is lacking on the effects of hormone replacement therapy in women with diabetes, especially during moderate chronic hyperglycemia.

Objectives: To study the effects of HRT on the lipid profile and the low density lipoprotein subclass distribution in women with type 2 diabetes under satisfactory and non-satisfactory glycemic control.

Methods: Fifty-four postmenopausal women after a 6 week run-in diet were randomized to receive either placebo(HbAlc <8%, n=13 HbAlc >8%, n=17) or HRT (HbAlc<8%, n=11 HbAlc >8%, n=13) for 12 weeks. HRT consisted of cyclical conjugated estrogens 0.625 mg/day plus medrogestone 5 mg/day. At the beginning and at the end of each treatment period the LDL subclass distribution was estimated by density gradient ultracentrifugation.

Results: At the baseline and during the study, the HbAlc level was significantly higher in hyperglycemic patients than in the near-normoglycemic controls (baseline 10.2±2.9 vs. 6.5±0.7%, P<0.01). They showed a trend for higher total and LDL cholesterol, triglycerides and lower high density lipoprotein-cholesterol compared to near-normoglycemic con­trols, as well as significantly higher triglyceride concentrations in very low density lipoprotein, intermediate density lipoprotein and LDL-1 particles and cholesterol content in LDL-1 and -2 particles. HRT decreased LDL-cholesterol in both groups. In the normoglycemic patients a small increase in HbAlc was observed (6.5±0.7 vs. 7.4+1%, P=004). In all cases, HRT did not modify the proportion of LDL represented by denser LDLs.

Conclusions: HRT did not modify the LDL subclass distribution, even in the presence of moderate chronic hyperglycemia in women with type 2 diabetes.