Birger Wolff

Association Between High Serum Ferritin Levels and Carotid Atherosclerosis in the Study of Health in Pomerania (SHIP)

Background and Purpose— Several studies have provided evidence for a relationship between body iron load and cardiovascular disease. We analyzed the association of serum ferritin levels with carotid atherosclerosis. Methods— We assessed intima-media thickness and plaque prevalence in the carotid arteries by high-resolution ultrasound among 2443 participants (1200 women; age, 45 to 79 years) in the Study of Health in Pomerania (SHIP), a population-based study in northeast Germany. Results— In multivariate analysis, serum ferritin levels were not independently associated with carotid intima-media thickness among women or men. In contrast, the relationship between serum ferritin levels and carotid plaque prevalence was significant among men (odds ratio per 1-SD increase of serum ferritin levels, 1.33; 95% confidence interval, 1.08 to 1.44) yet not among women (odds ratio, 1.29; 95% confidence interval, 0.98 to 1.75). However, both men and women showed a dose-response relation between serum ferritin levels and carotid atherosclerosis in which higher serum ferritin levels were associated with greater odds ratios for carotid plaque prevalence. Additionally, there was an interaction of serum ferritin levels with low-density lipoprotein (LDL) cholesterol (P =0.039) among men in which the association of serum ferritin levels with carotid plaque prevalence became stronger with increasing LDL cholesterol levels. Conclusions— Our study identified a relationship between serum ferritin levels and carotid atherosclerosis that was potentiated by LDL cholesterol. This relationship adds support to the hypothesis of a link between iron and cardiovascular disease.

Relation of Parity With Common Carotid Intima-Media Thickness Among Women of the Study of Health in Pomerania

Background and Purpose— Metabolic and hormonal changes associated with pregnancy and childbirth are assumed to contribute to the development of cardiovascular disease among women. We analyzed the association of parity with common carotid intima-media thickness (IMT), which has a predictive value of subsequent myocardial infarction and stroke. Methods— The Study of Health in Pomerania (SHIP), an epidemiological study of the general population in the northeast of Germany, included 1195 women aged 45 to 79 years. Mean and maximum far-wall IMT of the common carotid arteries were assessed by high-resolution ultrasound. All women were comprehensively characterized as to their reproductive history as well as to socioeconomic, behavioral, and biological risk factors. Results— There was a U-shaped association between the number of children (from 0 to ≥4) and mean and maximum IMT. Nulliparous women had the highest age-adjusted mean (0.81 mm [95% CI, 0.78 to 0.84]) and maximum IMT (1.04 mm [95% CI, 1.00 to 1.09]), and women with single parity the lowest (mean IMT, 0.73 [95% CI, 0.72 to 0.74]; maximum IMT, 0.91 mm [95% CI, 0.89 to 0.93]; P<0.001 versus nulliparity for both parameters). Stepwise multivariate adjustment for socioeconomic factors, lifestyle variables, and biological variables attenuated the magnitude of this association yet significance remained. Conclusions— Nulliparity and higher number of children are associated with increased carotid IMT. These findings add support to the hypothesis of a link between the reproductive history of women and cardiovascular disease.

Endothelial nitric oxide synthase Glu298Asp gene polymorphism, blood pressure and hypertension in a general population sample

Objective The Glu298Asp (E/D) polymorphism of the endothelial nitric oxide synthase (eNOS) gene has been related to hypertension. Since several studies have produced contradictory results, this issue is still subject to ongoing debate. We investigated the association of the eNOS E298D polymorphism with hypertension and with blood pressure (BP) in a large population-based sample of Caucasian ethnicity. Design Cross-sectional study in a random sample of the general population. Methods The eNOS E298D polymorphism was determined by 5′-exonuclease assay among 4219 participants aged 20–79 years of the Study of Health in Pomerania (SHIP). Results The percentages of the EE298, ED298 and DD298 genotypes were 49.2, 42.0 and 8.8%, respectively. The D allele frequencies did not differ between the groups of normotensive and hypertensive subjects (29.7 versus 29.9%, P = 0.812). Similarly, no association could be established between E298D genotype and prevalent hypertension, neither for D allele carriership (multivariate odds ratio 0.97, 95% confidence interval 0.83–1.12) nor for DD homozygosity (multivariate odds ratio 1.10, 95% confidence interval 0.84–1.43). Likewise, genotype groups did not differ as to the distribution of systolic (ANCOVA P = 0.917) or diastolic BP values (ANCOVA P = 0.657). Nearly identical results were obtained if the analyses were repeated sex-specifically or if subjects on antihypertensive medication were excluded. Conclusion In a population-based cohort of Caucasians covering a broad age range, the eNOS E298D polymorphism is neither associated with prevalent hypertension nor with systolic or diastolic BP. These results do not support the hypothesis that the E298D polymorphism contributes to the genetic susceptibility to hypertension.

Are serum thyrotropin levels within the reference range associated with endothelial function

AIMS High serum thyrotropin (TSH) levels within the reference range might be associated with an increased cardiovascular risk. In the present study, we investigated the association between serum TSH levels and flow-mediated dilation (FMD) as a measure of endothelial dysfunction. METHODS AND RESULTS The study population comprised 1364 subjects (670 women) aged 25-85 years with serum TSH levels between 0.25 and 2.12 mIU/L recruited from 5-year follow-up of the Study of Health in Pomerania. No interventions were performed. Measurements of FMD and nitrate-mediated dilation (NMD) were performed in the supine position using standardized ultrasound techniques. FMD and NMD values below the median of each distribution were considered decreased. Analyses adjusted for age, sex, smoking, and systolic and diastolic blood pressure revealed a non-significant inverse trend between serum TSH levels and FMD (P = 0.130). Subjects with serum TSH levels above the highest quartile had lower median FMD values relative to subjects with serum TSH levels below the lowest quartile (4.86 vs. 5.43%, P < 0.05). A linear inverse trend between serum TSH levels and decreased FMD barely missed statistical significance (P = 0.138). Subjects with high serum TSH levels had higher odds of decreased FMD relative to subjects with low serum TSH levels (odds ratio 1.42; 95% confidence interval 1.02; 1.96; P < 0.05). These associations were more pronounced in men than in women. There were no such associations for NMD. CONCLUSION Serum TSH levels within the upper reference range are associated with impaired endothelial function. Our findings contribute to the discussion on whether the upper TSH reference limit should be redefined.

Endothelial nitric oxide synthase Glu298→Asp polymorphism, carotid atherosclerosis and intima-media thickness in a general population sample

The Glu 298 → Asp (E298D; 894G → T) polymorphism of eNOS (endothelial nitric oxide synthase) has been related with cardiovascular disease. In the present study, we investigated the association of Glu 298 → Asp with atherosclerotic plaques in different carotid vessel segments and with carotid IMT (intima-media thickness). The Glu 298 → Asp eNOS polymorphism was determined by 5 � -exonuclease assay among 2448 participants of the SHIP (Study of Health in Pomerania). Mean and maximum common carotid IMT, as well as carotid atherosclerosis, were measured by high-resolution ultrasound. The Asp/Asp 298 genotype was associated with an increased risk of atherosclerotic plaques at the level of the common carotid arteries [multivariate odds ratio, 1.57 and 95 % CI (confidence interval), 1.05–2.34; P = 0.025], but not in the carotid bifurcations or internal or external carotid arteries. Glu 298 → Asp genotype was not associated with carotid IMT in the whole sample. However, the Asp/Asp 298 genotype was independently associated with both higher mean [adjusted increase by 0.046 mm (95 % CI, 0.013–0.078); P = 0.006] and maximum carotid IMT [0.137 mm (95 % CI, 0.064–0.209); P < 0.001] in the low-risk group of subjects without carotid atherosclerosis. In conclusion, the Asp/Asp 298 genotype is associated with atherosclerosis in the common carotid arteries and, in a low-risk group, also with carotid IMT. This suggests that the association of the Glu 298 → Asp genotype with atherosclerosis in the carotid arteries is site-specific and is modified by overall cardiovascular risk.

Candidate genetic markers and the risk of restenosis after coronary angioplasty

The aim of the present study was to test for possible associations between candidate gene polymorphisms and the risk of restenosis and recurrent restenosis after percutaneous transluminal coronary angioplasty (PTCA) without stenting. We followed up 511 PTCA patients, and restenosis and recurrent restenosis were defined according to angiographical criteria. Genotyping of the beta-fibrinogen -455 G/A, glycoprotein (GP) IIIa PlA1/PlA2, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, factor V Leiden 1691 G/A, tumour necrosis factor alpha (TNFalpha) -238 G/A, TNFalpha -308 G/A, interleukin (IL)-1alpha -889 C/T, IL-1beta -511 C/T, methylenetetrahydrofolate reductase (MTHFR) 677 C/T and endothelial nitric oxide synthase (eNOS) 4 b/a gene polymorphisms was performed by PCR and restriction-fragment-length-polymorphism-based techniques. One hundred and sixty patients (31.3%) developed restenosis and in 130 of these patients, of whom 123 were available for analysis, a second PTCA without stenting was performed. Of these patients, 35 (28.5%) developed recurrent restenosis. None of the investigated genotypes were associated with the risk of restenosis or recurrent restenosis after PTCA. The degree of stenosis before and immediately after PTCA and the severity of the lesion were independent predictors for restenosis after PTCA. In conclusion, there was no association between the beta-fibrinogen -455 G/A, GP IIIa PlA1/A2, PAI-1 4G/5G, factor V Leiden 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent restenosis after repeated PTCA.