[DIAGNOSIS AND TREATMENT OF ELEVATED LIPOPROTEIN(A) IN ISRAEL: CONSENSUS STATEMENT FROM THE ISRAEL SOCIETY FOR RESEARCH, PREVENTION AND TREATMENT OF ATHEROSCLEROSIS AND ISRAEL SOCIETY FOR CLINICAL LABORATORY SCIENCES].

INTRODUCTION: Lipoprotein(a) [Lp(a)] is composed of 2 major protein components, a low-density lipoprotein (LDL) cholesterol-like particle containing apolipoprotein B (apo B) that is covalently bound to apolipoprotein(a). Its level is predominantly genetically determined, and it is estimated that 20% to 25% of the population have Lp(a) levels that are associated with increased cardiovascular risk. Elevated Lp(a) is related to increased vascular inflammation, calcification, atherogenesis and thrombosis, and is considered an independent and potentially causal risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis. Recent data demonstrate that Lp(a) testing has the potential to reclassify patients' risk and improve cardiovascular risk prediction, and therefore could inform clinical decision-making regarding risk management. Statins and ezetimibe are ineffective in lowering Lp(a) levels, whereas proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have a modest effect on Lp(a) reduction. Nevertheless, RNA interference-based therapies with potent Lp(a)-lowering effects are in advanced stages of development, and clinical trials are underway to confirm their benefit in reducing cardiovascular events. This scientific consensus document was developed by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, and the Israeli Society for Clinical Laboratory Sciences, in order to create uniformity in Lp(a) measurement methods, indications for testing and reporting of the results, aiming to improve the diagnosis and management of elevated Lp(a) in clinical practice.

Hemoglobin A1C as a prognostic factor and the pre-diabetic paradox in patients admitted to a tertiary care medical center intensive cardiac care unit : The Jerusalem platelets thrombosis and intervention in cardiology (JUPITER-6) study group.

BACKGROUND: Hemoglobin A1C (HbA1c) is a form of glycated hemoglobin used to estimate glycemic control in diabetic patients. Data regarding the prognostic significance of HbA1c levels in contemporary intensive cardiac care unit (ICCU) patients is limited. METHODS: All patients admitted to the ICCU at a tertiary care medical center between January 1, 2020, and June 30, 2021, with documented admission HbA1c levels were included in the study. Patients were divided into 3 groups according to their HbA1c levels: < 5.7 g% [no diabetes mellitus (DM)], 5.7-6.4 g% (pre-DM), ≥ 6.5 g% (DM). RESULTS: A total of 1412 patients were included. Of them, 974 (69%) were male with a mean age of 67(± 15.7) years old. HbA1c level < 5.7 g% was found in 550 (39%) patients, 5.7-6.4 g% in 458 (32.4%) patients and ≥ 6.5 g% in 404 (28.6%) patients. Among patients who did not know they had DM, 81 (9.3%) patients had high HbA1c levels (≥ 6.5 g%) on admission. The crude mortality rate at follow-up (up to 1.5 years) was almost twice as high among patients with pre-DM and DM than in patients with no DM (10.6% vs. 5.4%, respectively, p = 0.01). Interestingly, although not statistically significant, the trend was that pre-DM patients had the strongest association with mortality rate [HR 1.83, (95% CI 0.936-3.588); p = 0.077]. CONCLUSIONS: Although an HbA1c level of ≥ 5.7 g% (pre-DM & DM) is associated with a worse prognosis in patients admitted to ICCU, pre-DM patients, paradoxically, have the highest risk for short and long-term mortality rates.

[TREATMENT OF HOMOZYGOTES OF FAMILIAL HYPERCHOLESTEROLEMIA: RECOMMENDATIONS OF THE ISRAELI SOCIETY OF ATHEROSCLEROSIS].

INTRODUCTION: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder caused by mutations affecting the function of the LDL receptor. In the Israeli population, the carrier heterozygote state is quite common, with the prevalence of 1:250, and the estimated prevalence of homozygote (hoFH) patients is 1:500,000. The life span of untreated hoFH patients is significantly shortened due to premature atherosclerosis and cardiovascular mortality. The basis of the appropriate treatment for hoFH is aggressive lipid lowering therapy from an early age and therefore, our approach is intensive LDL-C lowering as soon as the diagnosis is made. We recommend referring patients with hoFH to lipid-specialist clinics .We recommend genetic evaluation to confirm the diagnosis and cascade screening of family members for heterozygosity. Lipid goals are as recommended by the European Atherosclerosis Society. Aggressive and low as possible LDL-C targets (at least 50% reduction) are recommended. The initial treatment is high-dose potent statin and additional ezetimibe10 mg daily. PCSK9 inhibitor - Evolocumab is a novel additional option for hoFH with residual LDL receptor activity. The most effective method of reduction of plasma LDL levels is LDL-C apheresis. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that should be added to reduce the frequency of the apheresis procedures.

[UPDATED ISRAELI GUIDELINES FOR THE TREATMENT OF DYSLIPIDEMIA 2020].

INTRODUCTION: Despite the impressive decline in mortality from atherosclerotic cardiovascular diseases (ASCVD), these diseases still account for a large proportion of the overall morbidity and mortality worldwide. A vast amount of research has demonstrated the key role played by circulating lipoproteins, and especially low-density lipoprotein (LDL), in the etiology of atherosclerosis, and numerous studies have proven the efficacy of interventions that lower the atherogenic lipoproteins in reducing morbidity and mortality from ASCVD. While previous guidelines placed an emphasis on the use HMG-CoA reductase inhibitors (statins) for the treatment of dyslipidemia, recent studies have shown that other LDL cholesterol lowering drugs, including ezetimibe and the PCSK9 inhibitors, can provide additional benefit when used in combination with (and in certain cases instead of) statins. These studies have also shown that blood LDL cholesterol levels lower than previously recommended targets provide additional benefit, without evidence of a threshold beyond which the benefit ceases and without excess adverse effects. The updated guidelines were formulated by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, the Israel Society of Internal Medicine, the Israeli Heart Association, the Israeli Neurology Association and the Israel Association of Family Medicine. They provide recommendations for revised risk stratification of patients, novel target goals, and the use of evidence-based treatment and follow-up strategies with reference to specific patient sub-groups.

[THE IMPACT OF A COMMUNITY INTERVENTION PROGRAM IN ISRAELI WORKSITES TO REDUCE THE RISK OF CARDIOVASCULAR DISEASES].

INTRODUCTION: Atherosclerosis is the main cause of cardiovascular (CV) morbidity and mortality in the western world. Detection and treatment of risk factors (such as hypertension, dyslipidemia and diabetes mellitus) reduce CV events. We have shown cost utility in reducing these CV risk factors in community clinics and community centers. AIMS: In this paper we focused on community workplaces. METHODS: We included 1011 workers in 15 worksites in the study. All workers were analyzed for CV risk factors and included in 6 months of intervention in their worksite in order to reduce the burden of CV risk factors. RESULTS: Significant reduction was noted in the percentage of high risk patients from 43.7% to 27.8% to 24.7% after 3 and 6 months respectively (p<0.05), in the percentage of workers with high weight circumference, high blood pressure, smokers, and in high body mass index (>30g/m2 ). CONCLUSIONS: Interventions in community workplaces can improve the CV risk factors profile and thus should be implemented as broadly as possible.

Normal weight diabetic patients versus obese diabetics: relation of overall and abdominal adiposity to vascular health.

OBJECTIVE: The present study investigated the impact of overall obesity defined by BMI and abdominal obesity defined by WC on vascular atherosclerotic changes in obese and normal weight diabetic subjects. DESIGN AND METHODS: 285 subjects were divided according to presence diabetes mellitus (DM) and obesity: Group 1 included 144 nonobese subjects without DM; Group 2 consisted of 141 type 2 diabetic patients. Then diabetic patients were divided into two groups according to presence of overall obesity, defined by BMI and furthermore, abdominal obesity, defined by waist circumference (WC). Pulse wave velocity (PWV) and augmentation index (AI) were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). RESULTS: Between Group Comparisons by BMI: Diabetic subjects with and without overall obesity did not differ from one another in terms of AI and PWV. CONCLUSIONS: Abdominal obesity defined by WC was associated with significantly higher AI and PWV in in both diabetic men and women; whereas overall obesity defined by BMI did not predict adverse vascular changes in this study population. Abdominal obesity was associated with an adverse effect on blood vessels, independently of age, sex, blood pressure, fasting glucose and BMI.

Comparative Pharmacokinetic Assessment of Innovative Sublingual, Rectal and Vaporizer Cannabis Products Versus Approved Cannabis Products in Healthy Volunteers.

Background: Over the last years, there is a dramatic increase in the use of medical cannabis products for an expanding range of clinical indications. The type of the drug product and its administration route affect substantially the rate and the extent of absorption of cannabinoids and the effects induced by them in the patients. The current challenge for the cannabis pharmaceutical industry is to develop formulations that allow predictable and stable absorption of cannabinoids. This article reports the results of the clinical trial that investigated the pharmacokinetics (PKs) of innovative cannabis products in healthy volunteers. Materials and Methods: This was a single-center study with a single-dose, randomized, crossover, partially blinded controlled design. Each of the 12 healthy volunteers received 8 different products, of the 10 products that were assessed in this trial: novel sublingual (SL) tablet, vaporizer, and rectal products, comparator products (Sativex® and oil-based oromucosal products), and placebo products. Serial blood samples were collected, plasma concentrations of the THC, 11-OH-THC, and CBD were quantified and subjected to noncompartmental PK analysis. Results: Novel medical cannabis products that were investigated in the study induced substantial exposure of the volunteers to the active ingredients, had more rapid absorption, and in some cases also less variable absorption of THC and CBD, in comparison with the approved comparison products. The bioavailability of the novel SL tablet-based and suppositories products was somewhat lower than that of the oromucosal products. The vaporizer provided immediate systemic absorption with highest maximal concentration. The safety profile of the novel cannabis products, namely vaporizer, SL tablets, and suppositories, was not inferior to the Sativex and oil-based oromucosal formulations. Conclusions: The novel cannabis products that were assessed in this study have PK properties that may be advantageous for management of specific medical conditions or in specific subgroups of patients that are prescribed medical cannabis.

Sitagliptin pretreatment in diabetes patients presenting with acute coronary syndrome: results from the Acute Coronary Syndrome Israeli Survey (ACSIS).

BACKGROUND: Chronic treatment with currently available oral hypoglyemic medications may result in a differential effect on the clinical presentation of diabetic patients with acute coronary syndrome (ACS). METHODS: We evaluated presentation characteristics and the risk for in-hospital complications and 30-day major adverse cardiovascular events (MACE) among 445 patients with diabetes mellitus enrolled in the Acute Coronary Syndrome Israeli Survey (ACSIS) 2010. Patients were categorized into 3 groups according to glucose lowering medications at time of admission for ACS: 1) DPP 4 inhibitors (as monotherapy or in combination; DPP4i), 2) Metformin (monotherapy or in combination, excluding DPP4i) and 3) other oral hypoglycemics. RESULTS: Patients in the DPP4i group displayed similar baseline clinical characteristics to the other 2 groups, with the exception of a younger age and a lower frequency of prior coronary heart disease and chronic renal failure. Medical therapy with DPP4i was associated with a significantly lower in-hospital complication rate (post MI angina, re-infarction, pulmonary edema, infections, acute renal failure and better KILLIP class) (9.7%), lower rates of 30-day MACE (12.9%) and a shorter hospital stay (5.4 ± 3.8 days) as compared with patients treated with metformin (24.4%, 31.6% and 5.6 ± 5.0 days respectively) or other oral hypoglycemic drugs (45.5%, 48.5% and 7.5 ± 6.5 days respectively). Consistently, multivariate logistic regression modeling revealed that treatment with DPP4i was associated with a lower risk for in-hospital complications (OR = 0.129, p = 0.002) and 30-day MACE (OR = 0.157, p = 0.002) compared with other oral hypoglycaemic therapy. CONCLUSIONS: Our data suggests that chronic treatment with DPP4i may have cardioprotective effects in diabetes patients presenting with acute coronary syndrome.

Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

BACKGROUND: Insulin resistance (IR) is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). Therefore, correction of IR is a relevant therapeutic target.We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin. METHODS: In randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI) was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia) at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined. RESULTS: In placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study.In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels.Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin. CONCLUSIONS: Metformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glycemic control-independent mechanisms.

MEasuring Nutrition risk in hospitalized patients: MENU, a hospital-based prevalence survey.

BACKGROUND: Depending on the definition used, malnutrition is prevalent among 20-50% of hospitalized patients. Routine nutritional screening is necessary to identify patients with or at increased risk for malnutrition. The Nutrition Risk Screening (NRS 2002) has been recommended as an efficient tool to identify the risk of malnutrition in adult inpatients. OBJECTIVES: To utilize the NRS 2002 to estimate the prevalence of malnutrition among newly hospitalized adult patients, and to identify risk factors for malnutrition. METHODS: During a 5 week period, all adult patients newly admitted to all inpatient departments (except Maternity and Emergency) at Wolfson Medical Center, Holon, were screened using the NRS 2002. An answer of "yes" recorded for any of the Step 1 questions triggered the Step 2 screen on which an age-adjusted total score > or = 3 indicated high malnutrition risk. RESULTS: Data were obtained from 504 newly hospitalized adult patients, of whom 159 (31.5%) were identified as being at high risk for malnutrition. Malnutrition was more prevalent in internal medicine than surgical departments: 38.6% vs. 19.1% (P < 0.001). Body mass index was within the normal range among subjects at high risk for malnutrition: 23.9 +/- 5.6 kg/m2 but significantly lower than in subjects at low malnutrition risk: 27.9 +/- 5.3 kg/m2 (P < 0.001). Malnutrition risk did not differ by gender or smoking status, but subjects at high malnutrition risk were significantly older (73.3 +/- 16.2 vs. 63.4 +/- 18.4 years, P < 0.001). Total protein, albumin, total cholesterol, low density lipoprotein-cholesterol, hemoglobin and % lymphocytes were all significantly lower, whereas urea, creatinine and % neutrophils were significantly higher in patients at high malnutrition risk. CONCLUSIONS: Use of the NRS 2002 identified a large proportion of newly hospitalized adults as being at high risk for malnutrition. These findings indicate the need to intervene on a system-wide level during hospitalization.

[Prevention and treatment of atherosclerosis and cardiovascular diseases].

Atherosclerosis is one of the main causes of morbidity and mortality world-wide and specifically in Israel. These guidelines update the previous guidelines of the Israeli Society for Research, Prevention and Treatment of Atherosclerosis, published in 2005. The need for an update is based on new scientific data published in recent years necessitating changes in the recommendations for preventing and treating atherosclerosis. These guidelines were written in collaboration between all the societies outlined here and the content of this statement was approved by the delegates of these societies. The recommendations were written taking into consideration guidelines published by other international medical societies and also the specific needs of the Israeli medical system. Due to limitations of space, in the current paper we present: assessment of cardiovascular risk, smoking cessation and the treatment of dyslipidemia. Other sections including: recommendations to the general population, nutritional and physical activity recommendations, treatment of hypertension, prevention of ischemic stroke and the metabolic syndrome are available at http://www.ima.org.il/harefuah.

Intensification of diabetes treatment with long-acting insulin shows no benefit over other diabetes treatment.

BACKGROUND: Control of diabetes is challenging, and frequent treatment changes are needed. OBJECTIVE: To study the effect of the recommendation to start insulin glargine or insulin determir (long-acting insulin treatment, LAI) at discharge from hospital, on glucose control in the community setting. METHODS: Included were type II diabetes patients who were referred to and received a consultation from the hospital diabetes clinic during their hosptialization, as part of a routine consultation for diabetes management. During the visit, all patients were recommended long-acting insulin-based treatment, as inpatient treatment and at discharge. Follow-up was done by the primary physician in the community or by a community-based diabetes clinic. Glycosylated hemoglobin, glucose levels and other laboratory tests were obtained from the community health records before hospitalization and 6-12 months later. Medical treatment was ascertained by reviewing the actual usage of prescriptions. RESULTS: Eighty patients (58% males, mean age 64.1 +/- 12.7 years) were included in the analysis. HbA1c levels were 10.1 +/- 2.4% before admission, but improved significantly at follow-up (8.6 +/- 2.2%, P < 0.001). Seventy-one percent of the patients were taking the LAI treatment and the rest were using non-LAI medications. Changes in diabetes control were similar between the LAI and non-LAL groups (HbA1c was reduced by 1.5 +/- 3.2% and 1.9 +/- 3.1% respectively). The rate of repeated admissions was also similar, averaging at 1.3 admissions for both groups, the minority of which were related to glucose control. CONCLUSIONS: Insulin glargine or determir-based treatment does not show any superiority over other anti-diabetes treatment. It is our opinion that this treatment should be used as tailored therapy and should not be recommended routinely to all patients.

Association of Contemporary Statin Pretreatment Intensity and LDL-C Levels on the Incidence of STEMI Presentation.

Constituting hypolipidemic and pleiotropic effects, statins stabilize coronary artery plaque and may prevent STEMI events. This study investigated the association between contemporary statin pretreatment intensity, low-density lipoprotein cholesterol (LDL-C) levels, and the type of acute coronary syndrome (ACS) presentation: STEMI vs. NSTE-ACS. Data were drawn from the ACS Israeli Survey (ACSIS), a biennial prospective national survey that took place in 2008-2018. The rate of STEMI vs. NSTE-ACS was calculated by statin use, including statin intensity (high-intensity statin therapy (HIST) and low-intensity statin therapy (LIST) prior to the index ACS event. Among 5103 patients, 2839 (56%) were statin-naive, 1389 (27%) used LIST and 875 (17%) used HIST. Statin pretreated patients were older and had a higher rates of co-morbidities, cardiovascular disease history and pretreatment with evidence-based medications. STEMI vs. NSTE-ACS was lower among HIST vs. LIST vs. statin-naive patients (31.0%, 37.8%, and 54.0%, respectively, p for trend < 0.001). Multivariate analysis revealed that HIST was independently associated with lower STEMI presentation (ORadj 0.70; 95% CI 0.57-0.86), while LIST (ORadj 0.92; 95% CI 0.77-1.10) and LDL-C < 70 mg/dL (ORadj 0.96; 95% CI 0.82-1.14) were not. In conclusion, among patients admitted with ACS, pretreatment with HIST was independently associated with a lower probability of STEMI presentation, while LIST and LDL-C < 70 mg/dL were not.

Relation of haptoglobin phenotype to early vascular changes in patients with diabetes mellitus.

Haptoglobin (Hp) is an antioxidant protein and the major susceptibility gene for atherosclerosis in diabetic patients. The effect of Hp phenotype on arterial compliance and metabolic and inflammatory parameters was investigated. Patients were divided into 3 groups according to Hp phenotype of Hp 2-2, Hp 2-1, and Hp 1-1. Arterial elasticity of large and small arteries was evaluated using the pulse-wave contour analysis method. The large-artery elasticity index (LAEI) was lower in patients with Hp 2-2 compared with Hp 1-1 (8.4 +/- 2.3 vs 12.6 +/- 4.1 ml/mm Hg x 100; p <0.0001). The difference in LAEIs between the Hp 2-1 and Hp 1-1 groups was also significant (9.9 +/- 2.6 vs 12.6 +/- 4.1 ml/mm Hg x 100; p = 0.025). The Hp 2-2 and Hp 2-1 groups did not differ from one another. The small-artery elasticity index (SAEI) was significantly lower in patients with Hp 2-2 compared with Hp 1-1 (2.8 +/- 1.0 vs 4.4 +/- 1.9 ml/mm Hg x 100; p = 0.004). Differences in SAEIs between patients with Hp 2-1 and Hp 1-1, as well as those with Hp 2-1 and Hp 2-2, were not detected. Systemic vascular resistance differed significantly across groups, driven by the difference between patients with Hp 2-2 and Hp 1-1. In conclusion, LAEI and SAEI were significantly lower and systemic vascular resistance was higher in homozygotes for the 2 allele (Hp 2-2) compared with patients with Hp 2-1 or Hp 1-1 phenotypes. Differences in arterial elasticity were detected despite the lack of by-phenotype differences in glycemic control, blood pressure, or presence of cardiovascular risk factors.

Vascular elasticity of systemic lupus erythematosus patients is associated with steroids and hydroxychloroquine treatment.

We studied the large and small artery elasticity (AE) and systemic vascular resistance (SVR) of systemic lupus erythematosus (SLE) patients according to treatment profile. Forty-one SLE patients (90% female, mean age 48.7 +/- 2.4 years) were compared to 96 healthy controls. The large and small AE and the SVR were derived from radial artery waveforms (model CR-2000, HDI Inc.). Patients were categorized into groups according to treatment: steroid (12), hydroxychloroquine (HCQ) (9), steroid+HCQ (16), and no-steroids-no-HCQ (4). The steroid group had reduced large AE and increased SVR as compared to the HCQ group (8.3 mmHg x mL x 10 and 18.4 dyne x sec x 10(-3) versus 13.7 and 14.4, respectively). Mean large AE and the SVR of the HCQ group was similar to that of the controls (11.8 mmHg x mL x 10 and 14.5 dyne x sec x 10(-3), respectively). Mean large AE and SVR of the steroid+HCQ group were better than the steroid group (10.4 mmHg x mL x 10 and 16.0 dyne x sec x 10(-3)). Patients that received steroids had higher rates of hypertension (36%) and diabetes (1%) compared to rest of the patients (15% and 0%, respectively). Small AE, blood pressure, CRP, and SLEDAI were similar between the groups. Among SLE patients, steroid treatment was associated with the highest degree of vascular damage, and HCQ was associated with the lowest degree of vascular damage. It is possible that the steroids are responsible in part to the increased large-vessel manifestations observed in these patients, and that HCQ might have a protective effect on the vessel wall.

Cost-utility analysis of a national project to reduce hypertension in Israel.

BACKGROUND: This study aims to calculate the health effects and costs of a proposed national hypertension prevention and control program. METHODS: Interventions are based on experience from our two programs: 10-year period of Ashkelon Hypertension Detection and Control Program (AHDC Program) and the Israel Blood Pressure Control (IBPC) program. The costs of a nationwide program were calculated based on economic data, training staff levels, course frequency and unit costs. RESULTS: Over the next 20 years, the program should decrease the risk in one-half of the treated hypertensive cases of the following ailments: cardiovascular events such as Acute Myocardial Infarction (AMI) and Unstable Angina Pectoris (UAP) by 16.0%, stroke by 41.2%, End stage renal disease (ESRD) by 50.0% and peripheral vascular disease (PVD) by 42.6%. In total, around 2,242 lives, 35,117 years of life or 24,433 disability adjusted life years will be saved due to decreased mortality.Program costs amount to $352.7 million. However savings ($537.6 million), from reduced medical treatment ($444.3 million) and reduced pharmaceutical use ($93.3 million) as a result of morbidity decreases, exceed costs by $185.0 million. CONCLUSION: The project which saves both lives and resources should be extended nation-wide to reach as wide a population as possible.

Molecular genetics of familial hypercholesterolemia in Israel-revisited.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel. METHODS: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes was done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping. RESULTS: Mean serum cholesterol was 7.48 ± 1.89 mmol/L and the mean serum LDL-C was 5.99 ± 1.89 mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q), in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C > A. The c.2479G > A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C, but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a "mild" FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p = 0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy. CONCLUSIONS: The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.

9-cis beta-carotene-rich powder of the alga Dunaliella bardawil increases plasma HDL-cholesterol in fibrate-treated patients.

The effect of fibrates on high density lipoprotein (HDL)-cholesterol levels is suggested to be mediated by its binding to peroxisome proliferator-activated receptor-alpha (PPARalpha). Upon ligand binding, PPARalpha heterodimerizes with the 9-cis retinoic acid receptor (RXR) and it is this heterodimer which regulates gene expression. We assessed the hypothesis that a combined treatment with fibrate plus 9-cis beta-carotene-rich powder of the alga Dunaliella bardawil, as a source of 9-cis retinoic acid, would improve the drug's effect on HDL-cholesterol levels. In an open-labeled first trial, 20 fibrate-treated men with plasma HDL-cholesterol levels below 40 mg/dl were given Dunaliella capsules, providing 60 mg beta-carotene/day, containing all-trans and 9-cis beta-carotene (1:1 ratio, w/w). Twenty-two fibrate-treated patients participated in a double-blind placebo-controlled second trial. Eleven patients were treated with Dunaliella capsules, and 11 patients were treated with beta-carotene-deficient Dunaliella capsules. Following 6 weeks of the dual treatment plasma HDL-cholesterol increased by 24.5 and 12.7% in the first and second trials, respectively (P=0.002 and 0.012). The dual treatment also increased HDL-cholesterol levels in human apolipoprotein A-I transgenic mice by 87.5% (P=0.021). The results show that a combination treatment of fibrate plus 9-cis beta-carotene-rich Dunaliella powder amplifies the effect of the drug on HDL-cholesterol levels.

Cardiovascular risk assessment and treatment to target low density lipoprotein levels in hospitalized ischemic heart disease patients: results of the HOLEM study.

BACKGROUND: Hypercholesterolemia control status is lacking throughout the western world. OBJECTIVES: To examine whether the treatment recommendations given to ischemic heart disease patients at hospital discharge are compatible with the guidelines of the Israeli medical societies and the U.S. National Cholesterol Education Program for coronary artery disease prevention; and to study the effects of brief educational sessions on the adherence of physicians with the guidelines. METHODS: We included consecutive IHD patients admitted to four central hospitals in Israel between 1998 and 2000. The study was conducted in two phases. In phase 1, we reviewed discharge letters to document treatment recommendations given to each patient. In phase 2 we educated the practitioners by reviewing the Israeli medical societies and the NCEP guidelines and the quality of their recommendations in phase 1, after which we reevaluated the discharge letters. RESULTS: The study included 2,994 patients: 627 in phase 1 and 2,367 in phase 2. Of the patients who needed cholesterol-lowering according to their low density lipoprotein levels, 37.4% were not prescribed such drugs at discharge (under-treatment group). This proportion was reduced by education to 26.6% (P < 0.001) in phase 2. Of the treated patients, 65.6% did not reach the target LDLgoal in phase 1 (under-dosage group) as compared to 60.2% in phase 2 (P = 0.23). In phase 2 there was an increase in the percent of patients reaching LDL levels <130 mg/day (69.3% vs. 63.8% of patients prescribed medication, P = 0.01), but the percent of patients reaching' LDL levels <100 was not different in phase 2 after adjusting for age and gender (the odds ratio for reaching target LDL was 1.16, with 95% confidence interval of 0.95-1.43). CONCLUSIONS: Physician recommendations to IHD patients discharged from hospital were suboptimal. We documented a high proportion of under-treated and under-dosaged patients. Brief educational sessions have a beneficial effect on the usage of statins; however, additional effort in guideline implementations is needed.