Molecular genetic basis of familial hypercholesterolemia in St. Petersburg, Russia

190

71st EAS Meeting Abstracts accepted for presentation in the abstract book

biceps + triceps/subscapular + suprailiac skinfolds ratio (BT/SS), subscapular/triceps ratio (S/T), body fat percentage (BF%) according to Siri's formula and waist/hip ratio (WHR) were calculated. Data were expressed as means, standard deviation (SD). There was estimated correlation between anthropometric parameters and systolic and diastolic blood pressure in two groups of children. A possible link between low birth weight, body fat distribution and blood pressure will be discussed in the presentation. EFFICACY AND SAFETY OF ATORVASTATIN IN THE TREATMENT OF PATIENTS WITH HYPERTRIGLYCERIDEMIA OF VARIOUS PHENOTYPES T.K. Peters, M. Rieger 1 , L. Shurzinske 1 , S. Myers 1, J.W. Nawrocki 1.

Parke-Dauis Company. Freiburg, Germany" Iparke-Dauis Pharmaceutical Research. Division of Warner-Lambert Company Ann Arbor, MI, USA Currently, treatment options for patients with hypertriglyceridemia are limited. Nicotinic acid is not well tolerated and is often contraindicated, and fibrates, while lowering TGs effectively, may not produce adequate LDL-C reductions in this patient population. There is, therefore, a need for effective monotherapy that would simplify treatment of hypertriglyceridemic patients and reduce the risk of adverse events often seen with combination therapy. Atorvastatin, a recent addition to the statin class, has demonstrated the ability to significantly reduce both LDL-C and TGs in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types lla and lib). The aim o f the current analysis was to assess the efficacy and safety of atorvastatin in patients with hypertrigtyceridemia of various phenotypes (Fredrickson types 111 and IV). Data were analysed from 81 atorvastatin- and 12 placebo-treated patients with hypertriglyceridemia. Patients had originally participated in one of nine clinical studies of between 4 and 32 weeks' duration and were categorized into three datasets for this reanalysis: Group 1 patients had confirmed familial dysbetalipoproteinemia (type III); Group 2 patients had isolated hypertriglyceridemia (type IV) based on baseline TG > 200 mg/dl and LDLC _< 160 mg/dl; Group 3 patients had hypertriglyceridemia with TG > 500 mg/dl, regardless of LDL-C levels. A total of 32 patients (23 atorvastatintreated and 9 placebo-treated) were common to Groups 2 and 3. All results are expressed as mean percentage changes from baseline. In Group I patients (n = 16), atorvastatin at doses of 10 and 80 mg/day decreased TG levels by 41% and 57%, and IDL-C + VLDL-C levels by 32% and 58%, respectively. In Group 2 patients (n = 40), atorvastatin at 10, 20 and 80 mg/day reduced TG levels by 25%, 32% and 40%, respectively. For the same atorvastatin doses, Group 3 patients (n = 48) showed TG reductions of 35%, 30
Medicine University of Turin. Italy Hypercholesterolemia is a known risk factor for cardiovascular disease and statins are more effective drugs for its reduction. This study aimed to evaluate the efficacy o f atorvastatin versus pravastatin, fluvastatin and simvastatin in patients with familiar heterozygote hypercholesterolemia in primary prevention and the efficacy of aturvastatin versus pravastatin and simvastatin in patients with familiar heterozygote hypercholesterolemia in secondary prevention. 15 patients (6 males, 48.6+5.7 years, BMI 24.24-2.5 kg/m 2, mean4-SD) with severe hypercholesterolemia (baseline: total cholesterol TC 386+92 mg/dL, LDL.-cholesterol 3004-98 mg/dL, HDL-cholesterol 55+18 mg/dL, triglycerides TG 1834-149 mg/dL) in primary prevention and

11 patients (7 males, 59.6+I 1.5 years, BMI 25.5+3.4 kg/m 2) dyslipidemic (baseline: TC 322+39 mgd, LDL 228 4- 45 mg/dL, HDL 644-33 mg/dL, TG 1474-23 mg/dL) in secondary prevention were studied. Patients in primary prevention were treated for three mounths with each drug after a wash out period, rather with a low diet cholesterol diet (step 2): period A fluvastatin 40 rag/day, period B pravastatin 20 mg/day, period C simvastatin 20 mg/day, period D atorvastatin 10 rag/day; patients in secondary prevention were treated for three mounths with each drug as follows: period 1 pravastatin 20 mg/day, period 2 simvastatin 40 mg/day, period 3 atorvastatin 40 mg/day). Statistical analysis was made with ANOVA and t-Student test. In primary prevention patients we observed a reduction in total cholesterol (period A 342 5:88 vs period B 3704-110 vs period C 304+79 vs period D 274--1-72, P < 0.001 period D vs baseline, C < 0.01 period D vs B, p < 0.05 period D vs A), in LDL (A 242-t-95 vs B 2854-105 vs C 2164-77 vs D 1944-74, p < 0.01 D vs baseline, p < 0.01 D vs B), an increase in HDL (A 66 + 18 vs B 58+16 vs C 624-11 vs D 58+17, p < 0.05 A vs baseline) and no significant variations in triglycerides" levels. We observed a decrease in LDL in secondary prevention group (period I 195 + 73 vs period 2 1684-50 vs period 3 149+26, p < 0.01 period 3 vs baseline, p < 0.05 period 2 vs baseline). All reductase inhibitors had the same tolerability. Atorvastatin produced cholesterol reduction comparable to or greater than the other statins in severe heterozygote hypercholesterolemic patients in primary prevention; in secondary prevention patients neither atorvastatin neither other statins achieved the NCEP goals. THE IMPACT OF HYPERTRIGLYCERIDAEMIA ON LDL CHOLESTEROL IN DIABETICS L.M. Loh, E.S. Tai, B.S. Chew, A.H.C. Kua 1, A.C.K. Fok, C.E. Tan. Lipid Unit, Department of Endocrinology." /Department of PatholoKv Singapore General Hospital. Singapore Diabetics are at increased risk of atherosclerosis and the threshold for initiating treatment for elevated LDL cholesterol would be lower. However diabetics often have hypertriglyceridaemia, invalidating the Friedewald formula. Previous LDL measurements include ultracentrifugation and immunoseparation. These are cumbersome and used in research only. Commercial direct LDL assays are now available for clinical use but its significance remains to be determined. We compared a detergent based homogenous assay (Cholestest~ LDL. Daiichi, Japan) and salt density gradient ultracentrifugation in a series of 175 diabetic patients in our centre. The homogenous assay (H) correlated highly with the ultracentrifugation method (L) (r = 0.90, H = 0.423 + 1.57L, p < 0.0005), and was unaffected by high triglyceride levels. The median triglyceride was 1.91 mmol/L (range 0.53 to 11.8 mmol/L), with 23 subjects having levels above 4.5 mmol/L We observed a trend of LDL decreasing as triglyceride rose. Examination of the difference between the 2 assays (H-L) yielded unexpected results. There was a positive correlation at triglyceride < 2.3 mmol/L and a negative correlation above 2.3 mmol/L (p < 0.00005). The homogenous LDL assay is comparable to beta quantification and thus measures the LDL and intermediate density lipoprotein (IDL) cholesterol whilst the LDL isolated by salt gradient ultracentrifugation measures only pure LDL. H-L is probably the IDL component. The classical delipidation pathway (VLDL-IDL-LDL) is retarded in hypertriglyceridaemic subjects. We suggest that enhanced clearance ofapolipoprotein B related particles via alternative pathways may be responsible for our observations. MOLECULAR GENETIC BASIS OF FAMILIAL HYPERCHOLESTEROLEMIA IN ST. PETERSBURG, RUSSIA E.I. Schwartz, M.Ju. Mandelshtam 1, Kh. Chakir, V.I. Golubkov 1, S.V. Kudinov, B.M. Lipovetskyi 1, V.O. Konstantinov 1, A.D. Denisenko 1, V.S. Gaitskhoki 1. St. Petersburg Institute of Nuclear Physics; t lnstitute.for

Experimental Medicine, St. Petersburg, Russia The molecular genetic basis of familial hypercholesterolemia (FH) in Russia is poorly known. Using PCR-SSCP procedure followed by sequencing, we have screened the selected exons of the low density lipoprotein (LDL) receptor gene for point mutations and minor deletions in 86 FH patients. We have identified 5 LDL receptor gene mutations, namely 347 delGCC, C127W, CI39G (exon 4a), delta G197 (exon 4b) and E397X (exon 9). All the mutations, besides deltaG197, were new and specific for Slavic patients and seems to be causative for FH phenotype in the families. One

71st EAS Congress and Satellite Symposia

71st EAS Meeting Abstracts accepted for presentation in the abstract book muhiexon 5 kb deletion of the LDL receptor gene was reported from St. Petersburg population previously, this mutation also unknown from other countries. Rapid tests for all the new mutations were developed based on PCR-restriction enzyme digestion assays or direct heteroduplex visualization in gels after electrophoresis of PCR products {mutations 347 delGCC and delta GI97). The enzymes used for mutation testing were as follows: Mva I for CI27W, Msp I for CI39G, Alu 1 for E397X. Mutations CI39G and deltaGI97 were recurrent, the latter responsible for 30% (7 out of 22) of independent FH cases in Jewish patients. According to our data spectra of the LDL receptor gene mutations in Russia has absolutely specific character. This research was supported by grant "Cholesterol reducers" MSGP #SRUS-01-98-SCH and by grants from Russian Fund of Basic Research. LIPID ALTERING EFFICACY O F SIMVASTATIN IN TYPE 111 HYPERLIPIDEMIA

191

Results: Baseline characteristics for diabetics (D) and non-diabetics (nonD) were similar. Median 6 week changes (% from baseline) in lipids were:

LDL-C D

VLDL-C

TG

HDL-C

non-D

D

non-D

D

non-D

D

non-D

PBO

5

I

-I

-5

-2

..-4

1

3

40 S 80

-29 -40

-31 -36

-.40 -49

-34 -43

-28 -33

-28 -33

9 13

12 16

S

Conclusions: Simvastatin is an effective lipid altering treatment in patients with type 2 diabetes and combined hyperlipidemia and provide qualitatively similar effects as in non-diabetic patients.

D. Hunninghake 1, D. Plotkin 2, G. Dujovne3. M. Stepanavage 2, L.M. Keilson4, M. Mereuri 2. For the Simvastatin in Combined

L A R G E AND DOSE DEPENDENT EFFECTS OF SIMVASTATIN 40 AND 80 MG/DAY IN COMBINED H Y P E R L I P I D E M I A

Hyperlipidemia Research Group: Ill:art Prevention Clinic, Minneapolis, MN: 2Merck Research Laboratories, Rahwgv, NJ; 3Midcontinent Clinical Trial Kansas Ci0,, KS; 4Center for Lipid and Cardiovascular Health, Portland, ME, USA

D.B. Hunninghake1 , D. Plotkin 2, M. Stepanavage2, H. Bays3, M.H. Davidson4, C.A. Dujovnes, L.M. Keilson°, S.G. Korenman7, D.G. Robertson 8, E.A. Stein9, S.R. Weiss1°, M. Mercuri 2. And the

Background: Type III hyperlipidemia or dysbetalipoproteinemia is a rare condition characterized by elevated remnant lipoproteins, and is associated with premature coronary and peripheral atherosclerosis. Patients have an apolipoprotein Ez/2 genotype which results in reduced apo E binding affinity to the low density lipoproten (LDL) receptor and delayed catabolism of lipoproteins. Effective lipid altering therapy is required to prevent atherosclerotic disease. Methods: Seven patients ( I black, 3 women, age 27-55 yrs), homozygous for the apo E2 gene and with a very low density lipoprotein (VLDL) to triglycerides (TG) ratio (VLDL/TG) > 2.5, were randomized to placebo, simvastatin 40 and 80 mg/day as part o f a larger (130 patients total) doubleblind, 3 period, 6 week, complete block crossover study. Results: Median baseline values [mg/dL, to convert to mmol/L, divide LDL and high density lipoproteio (HDL) by 38.6 and triglycerides (TG) by 88.6] and 6-week lipid effects (% change from baseline: A):

Simvastatin in Combined H),perli~idemia Research Group; I Heart Disease Prevention Clinic, Minneapolis; - Rahway: 3Louisville: 4Chicago; 5Kansas CiO,; 6portland; 7Los Angeles: 8Atlanta; 9Cincinnati; I°San Diego, USA to assess the lipid altering efficacy and safety o f simvastatin (S) 40and 80- mg/day in patients with combined hyperlipidemia (CHL, LDL-C > 130 mg/dL or (<4.2 mmol/L, and TG: 300-700 mg/dL or 3.4-7.9 retool/L). Methods: 130 patients (age: 53+10, women: 48%, type 2 diabetes: 16%) with CHL were recruited into a multicenter, double-blind, placebocontrolled, 3 period, 6 week, balanced cross-over study. Patients were randomized to one of 6 treatment sequences including placebo and S 40 and 80 mg/day. Results: The baseline values in mg/dL (mmol/L), and lipid changes (% change from baseline) are summarized below. Treatment with simvastatin was well tolerated.

Aim:

Tnglycerides ~

LDL-Cholesterof[ N

IDL + LDL-C Base A

IDL + VLDC-C apoE Base A Ba.~

(mg/dL)

(mg/dL)

Placebo $40 123 S 80

-8. I -49.8 -50. I

156

A

(mg/dL)

-3.8 -58.3 -59.5

72

TG Base

HDL-C Base A

A

(mg/dL)

9.5 -37.8 -50.4

411

Placebo 119

(m~dL)

3.5 -40.5 -38.2

31

- 1.6 6.7 6.7

Conclusions: Monotherapy with simvastatin is an effective lipid altering

treatment in patients with type 111 hyperlipidemia providing substantial lowering of total triglycerides and apo B containing lipoproteins rich in TG, while increasing HDL-C. SIMVASTATIN T R E A T M E N T IN PATIENTS W I T H TYPE 2 DIABETES AND C O M B I N E D H Y P E R L I P I D E M I A S.G. Korenman, E.A. Stein 2, D. Hunninghake3, M.H. Davidson4, LM. Keilson 5, M. Stepanavage 6, D. Plotkin 6, M. Mereuri 6. For the

Sinwastatin in Combined Hyperlipidemia Research Group; t UniversiO, of California, Los Angeles; :Metabolic and Atherosclerosis Research Center, Cincinnati; Heart Prevention Clinic, Minneapolis," 4Chicago Center for Clinical Research, Chicago; 5Center for Lipid and Cardiovascular Health, Portland; 6Endocrinology and Metabolism, Merck & Co. lnc, Rahway, USA Background: Diabetes is associated with a 2-4 increased risk o f coronary heart disease (CHD). In the Scandinavian Simvastatin Survival Study (4S), simvastatin reduced the risk of cardiovascular events in diabetics with CHD and hypercholesterolemia by 55%. Combined hyperlipidemia is a common lipid disorder in patients with diabetes and the use of statins in combination with other lipid lowering drugs often required. Availability of a new higher dose (80 mg) of simvastatin may provide effective monotherapy. Methods: A subset of 24 patients (11 women, mean age 54 yrs) with type 2 diabetes were randomized as part of a larger (total 130 patients) double-blind, 3 period, 6 week, complete block crossover study and treated with placebo, simvastatin (S) 40 and 80 rag/day.

S-40

120

A

N

Base

A

156 14.0) 156

2.1NS

120

389 14.4) 389

-3.5Ns 120

-28.9"* 120

(4.0) S-80

119

HDL-Cholasterol

Base

156

(4.0)

N

-27.8°° 120

14.4) -35.5""

121

391

(4.4)

Base

A

39.0 (1.0) 38.9

3.3" 13.1"°

(I.0) -33.0 °°

121

38.9

15.7 °"

(I.0)

t by ultracentnlegation.~Medianbaselineand % changereported.All ber,een treatmentcomparisor~ werestatisdca|lysignificantat p _<0.05.Withintreaunentcomparisons:NSnotsignificant;*p = 0.002; "'p < 0.001. Conclusions: Simvastatin is an effective treatment for CHL and exerts a beneficial effect across the lipoprotein profile. The reduction in TG was large, dose dependent and similar in magnitude to LDL-C. The effect on HDL-C was substantial and dose dependent.

C L I N I C A L IMPORTANCE O F SOME LIPID P A R A M E T E R S IN PRIMARY P R E V E N T I O N OF A T H E R O S C L E R O S I S IN YOUNG PEOPLE L.L. Faleiro 1, A. Forts:ca 2, M.O. Rodrignes2, M.C. Martins 2.

l Departamento de Cardiologia, IPR, Lisboa; 21nstituto Nacional de Safade, Lisboa, Portugal Cardiovascular diseases (CVD) have their origin in childhood when starts the atherosclerosis pathogen:sis under the influence of genetic and environment factors. Among these factors hyperlipidemia is one of the most important. So high total and LDL cholesterol, low HDL cholesterol concentrations in children and youngsters can be relevant for predicting men and v ~ m e n who will develop CVD being the clifiical follow up of those at risk extremely important at individual and public health levels through their treatment and monitoring. The authors decided so to screen a total o f 153 children and adolescents, both sexes, 4-19 years old by measuring total, LDL and HDL cholesterol. The laboratory methods for these parameters were: CHOD-PAP for total

71st EAS Congress and Satellite Symposia