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R G Westendorp

Publications and source records attributed to R G Westendorp.

At least 19 recordsLinked to original sources
PubMed1999

Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.

BACKGROUND: Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteraemia or meningitis without septic shock. We investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock. METHODS: We investigated 50 patients who survived meningococcal infection, and 131 controls from the same geographical region. Because we had no information on genotypes of patients who died, we also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the plasminogen-activator-inhibitor-1 gene (PAI-1). The 4G allele is associated with increased gene transcription in cell lines in vitro and with increased PAI-1 concentrations in carriers in vivo. FINDINGS: The allele frequencies of 4G and 5G were similar between patients and controls. However, the 4G/4G genotype was present in only 9% of relatives of patients with meningitis compared with 36% of relatives of patients with septic shock. The 5G/5G genotype was more common among relatives of patients with meningitis (31 vs 11%, p=0.001). Patients whose relatives were carriers of the 4G/4G genotype had a six-fold higher risk of developing septic shock than meningitis (odds ratio 5.9 [95% CI 1.9-18.0]) compared with all other genotypes. INTERPRETATION: Variation in the PAI-1 gene does not affect the probability of contracting meningococcal infection, but does influence the development of septic shock.

Adolescent↗
PubMed1999

Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure.

BACKGROUND: Long-term prognosis of patients with type-1 diabetes mellitus and end-stage renal failure appears to be better after kidney transplantation compared with dialysis. Controversy exists about the additional benefit of a simultaneously transplanted pancreatic graft. We studied the effect on mortality of simultaneous pancreas-kidney transplantation compared with kidney transplantation alone from regional differences in transplantation protocols. METHODS: All 415 patients with type-1 diabetes (aged 18-52 years) who started renal-replacement therapy in the Netherlands between 1985 and 1996 were included in the analysis. Patients were allocated to a centre based on their place of residence at onset of renal failure. In the Leiden area, the primary intention to treat was with a simultaneous pancreas-kidney transplantation, whereas in the non-Leiden area, kidney transplantation alone was the predominant type of treatment. All patients were followed up to July, 1997. Analyses, mortality, and graft failure were by Cox proportional-hazard model adjusted for age and sex. FINDINGS: Simultaneous pancreas-kidney transplantation was done in 41 (73%) of 56 transplanted patients in the Leiden area compared with 59 (37%) of 158 transplanted patients in the non-Leiden area (p<0.001). The hazard ratio for mortality after the start of renal-replacement therapy was 0.53 (95% CI, 0.36-0.77, p<0.001) in the Leiden area compared with the non-Leiden area. When just the transplanted patients were analysed the mortality ratio was 0.4 (95% CI 0.20-0.77, p=0.008) and was independent of duration of dialysis and early transplant-related deaths. Equal survival was found for patients on dialysis only. INTERPRETATION: These data support the hypothesis that simultaneous pancreas-kidney transplantation prolongs survival in patients with diabetes and end-stage renal failure.

Adult↗
PubMed1999

The definition of anemia in older persons.

CONTEXT: Whether hemoglobin concentrations defined as anemia by the World Health Organization (WHO) are associated with increased mortality in older persons is not known. OBJECTIVE: To investigate the association between hemoglobin concentration and cause-specific mortality in older persons. DESIGN: Community-based study conducted from 1986 to 1996 (follow-up period, 10 years). SETTING: Leiden, the Netherlands. PARTICIPANTS: A total of 1016 community residents aged 85 years and older were eligible and 872 agreed to have a blood sample taken. Hemoglobin concentration was measured in 755 persons (74%). MAIN OUTCOME MEASURES: Hemoglobin concentration, 10-year survival, and primary cause of death. According to the WHO criteria, anemia was defined as a hemoglobin concentration below 7.5 mmol/L (120 g/L) in women and below 8.1 mmol/L (130 g/L) in men. RESULTS: Compared with persons with a normal hemoglobin concentration, the mortality risk was 1.60 (95% confidence interval [CI], 1.24-2.06; P<.001) in women with anemia, and 2.29 (95% CI, 1.60-3.26; P<.001) in men with anemia. In both sexes, the mortality risk increased with lower hemoglobin concentrations. In persons without self-reported clinical disease at baseline, the mortality risk of anemia was 2.21 (95% CI, 1.37-3.57; P=.002). Mortality from malignant and infectious diseases was higher in persons with anemia. CONCLUSIONS: Anemia defined by the WHO criteria was associated with an increased mortality risk in persons aged 85 years and older. The criteria are thus appropriate for older persons. A low hemoglobin concentration at old age signifies disease.

Aged↗
PubMed1999

Protection against influenza after annually repeated vaccination: a meta-analysis of serologic and field studies.

BACKGROUND: According to common recommendations, influenza vaccination should be performed annually. It has been suggested that vaccination in previous years reduces vaccine efficacy in the long term. OBJECTIVE: To determine whether the protection of influenza vaccine decreases when vaccination is repeated annually. METHODS: Articles published between 1966 and 1997 were selected from MEDLINE. The end point for field studies was the influenza-related morbidity or mortality during influenza outbreaks (resulting in field protection rates). The end point for serologic studies was exceeding a protective postvaccination hemagglutination-inhibition titer (serologic protection rates). Protection rate differences between groups with single and multiple vaccinations were subjected to meta-analysis. RESULTS: Seven field studies (including 13 trials) supported the hypothesis that protection in multiple-vaccination groups is at least as good as that in single-vaccination groups. Ten trials with 5117 observations could be subjected to meta-analysis. The pooled protection-rate difference was close to 0 (1.1%; 95% confidence interval, -0.2% to 2.4%), thus detecting no difference between single or multiple vaccination. Twelve serologic studies (including 53 trials) showed heterogeneous results: 9 trials were significantly in favor of single vaccination, and 7 were in favor of multiple vaccination, but in most cases, there was no significant difference between the 2 vaccination groups. The pooled serologic protection-rate difference from 52 trials (12341 observations) was again close to 0 (1.7%; 95% confidence interval, -1.3% to 4.8%). CONCLUSIONS: We did not detect any evidence for a decreasing protection with annually repeated influenza vaccination. Annual vaccination should not be discouraged in populations at risk.

Antibodies, Viral↗
PubMed1999

Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort.

OBJECTIVES: We studied the contribution of putative risk genotypes at the angiotensin I-converting enzyme inhibitor (ACE D/D) and plasminogen activator inhibitor-1 (PAI-1 4G/4G) loci to all-cause and cardiovascular mortality in a population-based cohort. BACKGROUND: The ACE D/D and PAI-1 4G/4G genotypes have been consistently associated with elevated plasma activities of the gene products. Their role in cardiovascular disease, although explored intensively, is still equivocal. METHODS: The ACE and PAI-1 genotypes were determined in 648 subjects > or =85 years old. In a cross-sectional analysis, the genotype distributions in a subset of 356 elderly subjects who were born in Leiden, The Netherlands, were compared with those in 250 young subjects whose families originated from the same geographic region. In addition, the complete cohort of elderly subjects was followed over 10 years for all-cause and cardiovascular mortality and was stratified according to genotype. RESULTS: In the cross-sectional analysis, the ACE and PAI-1 genotype distributions were similar in elderly and young subjects. In the prospective follow-up study, however, the age-adjusted risk of fatal ischemic heart disease was increased threefold (95% confidence interval [CI] 1.2 to 7.6) in elderly men carrying the PAI-1 4G/4G genotype. The risk of all-cause mortality was not increased among elderly subjects carrying the PAI-1 4G/4G (relative risk [RR] 0.9, 95% CI 0.7 to 1.1) or the ACE D/D genotype (RR 0.9, 95% CI 0.7 to 1.1), nor did we observe elevated risks of death from all cardiovascular diseases combined. There was no interaction between the genotypes. CONCLUSIONS: The PAI 4G/4G genotype may be a risk factor for fatal ischemic heart disease in elderly men. The impact of moderately increased ACE and PAI-1 activities associated with the ACE D/D and PAI-1 4G/4G genotypes is too small to affect mortality in the general population.

Aged↗
PubMed1999

The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding?

OBJECTIVE: In order to determine whether screening of thyroid function is justified in patients with hypercholesterolaemia, we determined the prevalence of subclinical hypothyroidism at different levels of total plasma cholesterol in middle-aged men and women. DESIGN AND METHODS: 1200 participants were selected from a population based cross sectional study on risk factors for cardiovascular diseases. The participants were divided into three groups: total plasma cholesterol < 5 mmol/l, total plasma cholesterol 5-8 mmol/l, total plasma cholesterol > 8 mmol/l. Each group was comparable in size and sex distribution. Subclinical hypothyroidism was defined as plasma TSH levels higher than 4 mU/l, in the presence of normal free thyroxine (FT4(4)) concentration. RESULTS: Plasma samples of a total of 1191 participants were analyzed. The overall prevalence of subclinical hypothyroidism was 1.9% in men and 7.6% in women of middle age. In women the prevalence of subclinical hypothyroidism increased from 4.0 percent in the lowest, to 10.3 percent in the highest cholesterol stratum (P = 0.02). In men, the mean prevalence was 1.8 percent and roughly similar in the various strata. After age correction, an increase of 1 mU/l TSH in women was associated with an increase of 0.09 mmol/l total plasma cholesterol (95% confidence interval (CI) 0.02-0.16 mmol/l). A similar trend was found in men (0.16 mmol/l, 95% CI -0.02-0.34 mmol/l). CONCLUSIONS: In the population, the prevalence of subclinical hypothyroidism is up to 10 percent in middle aged women with high levels of total plasma cholesterol and may justify case-finding. In these women approximately 0.5 mmol/l of total plasma cholesterol can be attributed to the subclinical thyroid dysfunction. In men a similar correlation between thyroid dysfunction and total plasma cholesterol is seen, but the prevalence of thyroid dysfunction is considerably lower.

Cholesterol↗
PubMed1999

Risk factors for acquisition of Serratia marcescens in a surgical intensive care unit.

Between January 1996 and May 1997, a four-fold increased rate of isolation of Serratia marcescens was observed amongst patients admitted to the surgical Intensive Care Unit (SICU) of the Leiden University Medical Center compared to the preceding years. Random amplification of polymorphic DNA showed the involvement of genotypically distinct strains, implicating multiple different sources. After improvement of hygienic measures the frequency of isolation of S. marcescens returned to baseline. A case-control study was performed to assess patient-related risk factors for acquisition of S. marcescens. Nineteen cases and 38 controls were included. Hospital- and SICU-stay were significantly longer in case patients than in controls. By univariate analysis, statistically significant differences were found in body weight, the duration of mechanical ventilatory support, the cumulative use of antimicrobial agents, the use of aminoglycosides, parenteral nutrition and tube feeding. The sum of the number of days per invasive device (deep intravenous lines, arterial lines, wound drains and urinary catheters) was higher in cases than in controls (P = 0.08). Categorically, a cumulative number of device-days > 25 was a statistically significant risk factor for acquisition of S. marcescens. Multivariable logistic regression analysis showed that body weight, parenteral feeding and mechanical ventilation were independent predictors of acquisition of S. marcescens. As transmission of S. marcescens appears to be by the hands of personnel, the identified risk factors may act by necessitating an increased frequency and intensity of direct contacts.

APACHE↗
PubMed1999

Quality and quantity of the humoral immune response in healthy elderly and young subjects after annually repeated influenza vaccination.

Doubt about the serologic efficacy of annually repeated influenza vaccination prompted investigations into the course of hemagglutination-inhibiting (HI), IgG, and IgA antibody titers and the IgG and IgA avidity index to influenza A/Taiwan/1/86 and A/Beijing/353/89 after annual vaccination. Fifty-four healthy elderly persons >70 years of age and 24 healthy young adults <30 years of age received standard influenza vaccine during 3 consecutive years. On average, prevaccination HI, IgG, and IgA titers to both influenza virus strains increased >=4 fold between the first and the third vaccination (analysis of variance, P<.001). The postvaccination HI and IgG titers remained unchanged after annual vaccination. The avidity index of IgG and IgA antibodies increased somewhat after annual vaccination, although the increase was statistically significant only in the young subjects. These data indicate that annual influenza vaccination of healthy elderly and young subjects results in an overall increase in protective antibodies.

Adolescent↗
PubMed1999

Ephelides are more related to pigmentary constitutional host factors than solar lentigines.

Ephelides and solar lentigines are benign pigmented spots, which are currently associated with an increased risk of skin cancer. These two pigmented spots are known to be discriminated by their clinical, histological, and electron microscopic characteristics, even though occasional misclassification can occur because of their similarity. It has also been questioned whether these spots are not one and the same. In this study, we have attempted to differentiate between these two pigmented spots with the use of a standardized protocol for clinical examinations on 272 healthy volunteers, paying particular consideration to their pigmentary and constitutional host factors. We found that solar lentigines 1) are more prevalent than ephelides, 2) increase in prevalence and number with higher age, and 3) are most prevalent on the trunk and occur more frequently in males than in females. A trend is also observed whereby ephelides 1) loose their prevalence with age, 2) become equally distributed on the face, arms, and trunk, and 3) occur more frequently in females. An intimate association of ephelides, but not solar lentigines, has been found with hair color and skin type. All of these findings are in agreement with most of those reported in the literature, supporting the view that ephelides and solar lentigines are different types of pigmented lesions.

Adult↗
PubMed1999

Mortality in patients with epilepsy: 40 years of follow up in a Dutch cohort study.

To investigate the extent of and the causes of excess mortality in patients with epilepsy, mortality was studied in a cohort of patients with newly diagnosed epilepsy over an extended follow up period. All patients (both inpatients and outpatients) of the Instituut voor Epilepsiebestrijding in Heemstede, the Netherlands between 1953 and 1967 were included in the study. Complete follow up was obtained for 1355 patients, 746 men and 609 women. The mean follow up was 28 years (range 6 months-41 years). In total, 38 665 person years were surveyed, in which 404 patients died. All cause mortality was threefold increased (risk ratio (RR) 3.2; 95%CI 2.9-3. 5), and was only slightly higher for men than for women. Mortality was highest under 20 years of age (RR 7.6; 95%CI 6.5-8.7), and during the first 2 years of follow up (RR 16; 95%CI 12-20). Mortality directly related to epilepsy accounted for 18 of the 53 deaths in the first 2 years after diagnosis, which is equivalent to an incidence rate of 6.8 per 1000 person-years (95% CI 4.1-10). After 2 years 110 of the 351 deaths could be attributed to epilepsy itself, or were epilepsy related, with an incidence rate of 3.1 per 1000 person-years (95% CI 2.5-3.6). The data presented suggest that the increased mortality risk in patients with epilepsy is attributable in part to epilepsy itself, and is predominantly present at younger age and early after diagnosis. However, the absolute risk is moderate.

Cause of Death↗
PubMed1999

Thermolabile methylenetetrahydrofolate reductase gene and the risk of cognitive impairment in those over 85.

OBJECTIVES: Previous reports have shown raised plasma concentrations of homocysteine in older persons with cognitive impairment. This may be caused by environmental and genetic factors. The relation between cognitive function and a common ala/val mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was studied in those over 85. Homozygous carriers of this mutation are characterised by a lifelong exposure to moderately raised plasma concentrations of homocysteine. METHODS: In the Leiden 85-plus Study, a population based study of persons aged 85 years and over, the score on the mini mental state examination (MMSE) and the presence of dementia dependent on the MTHFR genotypes were compared in 641 participants (456 women, 185 men) at baseline. In addition, the association between the MTHFR genotype and cognitive decline was studied by re-examining cognitive function of 172 participants without dementia at baseline after a median follow up of 4.0 years. RESULTS: At baseline, carriers of the ala/ala genotype had a median MMSE score of 27 points (interquartile range (IQR) 21.5-29), for the ala/val genotype it was 26 points (IQR 20-29), and for the val/val genotype it was 27 points (IQR 20-28.3) (p=0.3). The prevalence of dementia was also not significantly different for the various genotypes (ala/ala 22%, ala/val 28%, val/val 27%; p=0.4). None of the carriers of the val/val genotype without cognitive impairment at baseline developed dementia during the follow up. CONCLUSIONS: Although previous studies have shown that older persons with cognitive impairment have raised plasma concentrations of homocysteine, homozygosity for the ala to val mutation in the MTHFR gene is not a genetic risk factor for cognitive impairment in persons aged 85 years and over.

Aged↗
PubMed1999

The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM.

BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes.

Adult↗
PubMed1998

Determination of tumour necrosis factor-alpha and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation.

Ex vivo production of cytokines as determined by whole blood stimulation and supernatant ELISA is partly determined by heritability. To assess the ability of this system to distinguish between high and low producers the laboratory error and individual variation were investigated. Whole blood samples from healthy volunteers were collected using endotoxin-free tubes and were incubated with 0 to 1000 ng/ml lipopolysaccharide concentrations for 4 and 24 h, and subsequently centrifuged. In the supernatants, TNF-alpha and IL10 were measured by ELISA. Coefficients of variation for the day-to-day variation in the blood sampling, transport and stimulation as well as in the whole blood stimulation per se ranged from 7.5% to 12.3%. The intra-individual variation was 15% (TNF-alpha) and 19% (IL10) in contrast to the inter-individual variation of, on average, 35%. No interchanging of ranks between high and low producers was observed after repeating the whole blood stimulation on distinct days. The whole blood stimulation system is able to distinguish high and low producers of TNF-alpha and IL10.

Blood↗
PubMed1998

[Roaming through methodology. VI. Medical perspective on the causes of death].

The Central Statistics Office (CBS) annually publishes the causes of death of decreased Dutch residents. It is generally assumed that the registration of causes of death is unreliable and provides only limited additional information. It is a fact that the physicians who perform the post mortems may supply incomplete or incorrect information. Hence, individual causes of death are sometimes coded incorrectly. This necessitates specific instruction of medical students. For studies of large groups, misclassification of individual causes of death is of less importance. However, the systematics of the registration has to be taken into account. It is important that causes of death are registered uniformly facilitating (inter)national comparisons. With the aid of a causes of death register, characteristics of (groups of) the population can be related to the distribution of the causes of death; at the level of the individual patient the causes of death may afford insight into causes and effects of disease. The latter is possible by a temporary link of patient data with the individual causes of death.

Cause of Death↗
PubMed1998

Interleukin 10 secretion in relation to human IL-10 locus haplotypes.

Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) shows large inter-individual variation in interleukin 10 (IL-10) secretion, which has been shown to have a genetic component of over 70%. Alleles at two microsatellite loci in the 4 kb immediately upstream of the human IL-10 transcription initiation site in 132 individuals from 56 Dutch families were defined and assigned as haplotypes. LPS-induced IL-10 secretion was measured by ELISA and related to the IL-10 promoter haplotypes present in 78 unrelated individuals obtained from these families. Analysis showed that LPS-induced IL-10 secretion from unrelated individuals varied with IL-10 promoter haplotypes (P = 0.024; Kruskal-Wallis test). Two observations were made in relation to secreted IL-10 levels and promoter haplotypes; first, those haplotypes containing the allele IL10.R3 were associated with lower IL-10 secretion than haplotypes containing any other IL10.R allele. Second, the haplotype IL10.R2/IL10.G14 was associated with highest IL-10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL-10 secretion. These data demonstrate that the ability to secrete IL-10 can vary in man according to the genetic composition of the IL-10 locus.

Alleles↗
PubMed1998

Anti-inflammatory cytokine profile and mortality in febrile patients.

BACKGROUND: An anti-inflammatory cytokine profile on whole-blood stimulation in vitro is associated with fatal outcome of meningococcal disease. We investigated whether an anti-inflammatory cytokine profile in the circulation is associated with adverse outcome in other infectious diseases. METHODS: We enrolled 464 consecutive patients (272 men, 192 women) who presented to hospital with fever (> or = 38.2 degrees C). On admission we measured plasma interleukin 10 (IL-10) and tumour necrosis factor alpha (TNF alpha), and collected clinical and microbiological data on the febrile illness, then followed up all patients for clinical outcome. FINDINGS: In at least 399 of the 464 patients fever was caused by infection. 33 patients died after a median hospital stay of 11 days (interquartile range 3-20). Concentrations of IL-10 were significantly higher in non-survivors (median 169 pg/mL [IQR 83-530]) than in survivors (median 88 pg/mL [42-235], p=0.042). When dichotomised around the median, the mortality risk was two times higher in patients who had high concentrations of IL-10 than in those with low concentrations (relative risk 2.39 [95% CI 1.07-5.33]), in patients with low and high concentrations of TNF alpha. In the 406 patients without haemodynamic deterioration in the first 24 h, IL-10 was higher and TNF alpha lower in patients who died than in those who survived. The ratio of IL-10 to TNF alpha was higher in non-survivors (median 6.9 [3.0-21.0]) than in survivors (median 3.9 [2.0-7.0], p=0.040). This ratio was highest in patients who died without underlying disease (median 21.5 [5.0-25.0]). Age, sex, and duration of fever before admission did not explain the differences in IL-10 and TNF alpha. INTERPRETATION: An anti-inflammatory cytokine profile of a high ratio of IL-10 to TNF alpha is associated with fatal outcome in febrile patients with community-acquired infection. Our findings caution against a widespread use of proinflammatory cytokine inhibition in patients with sepsis.

Adolescent↗
PubMed1998

Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations.

In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.

Anticholesteremic Agents↗