Bernhard Iglseder

The Metabolic Syndrome Is a Stronger Risk Factor for Early Carotid Atherosclerosis in Women Than in Men

Background and Purpose— The metabolic syndrome (MetS) is associated with an increased risk for subsequent development of type 2 diabetes mellitus, cardiovascular disease, and stroke. Type 2 diabetes increases the risk of stroke and coronary heart disease in women to a greater extent than in men, and thus the question arises whether there are sex differences in the association of early atherosclerosis and MetS. Methods— 1588 middle-aged Austrian subjects (1001 males, 587 females) were included in the present study. MetS was defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Early atherosclerosis was assessed by intima-media thickness (IMT) and extent of plaques (B-score) of the carotid arteries. Results— B-score and carotid artery IMT parameters were significantly higher in subjects with the MetS. After adjustment for established risk factors, the difference in B-score remained significant only in women. Computed common carotid artery IMT values using general linear model equations with age, body mass index, and low-density lipoprotein cholesterol as covariates displayed the highest values for men with MetS (811.8±9.5 &mgr;m). Women with MetS (797.6±15 &mgr;m) and men without the syndrome (788.8±5 &mgr;m) showed similar IMTs, whereas women without the MetS presented significantly lower values (735.6±7 &mgr;m). Among the subcomponents of the MetS, high-density lipoprotein cholesterol showed the strongest impact on IMT in men, whereas blood glucose ranked first in women. Conclusions— The effect of MetS on early atherosclerosis is more pronounced in females. The impact of the components of MetS on carotid IMT differs between men and women.

Plasma Adiponectin Levels and Sonographic Phenotypes of Subclinical Carotid Artery Atherosclerosis. Data From the SAPHIR Study

Background and Purpose— Adipose tissue produces and secretes a number of bioactive molecules, conceptualized as adipocytokines. Adiponectin has been identified as one of the adipocytokines, and hypoadiponectinemia was demonstrated in patients with obesity, diabetes mellitus, and coronary artery disease. Whether decreased adiponectin levels are cause or consequence is an important issue in the discussion on the association between adiponectin and atherosclerosis. In the present study, we investigated the association of plasma adiponectin levels with sonographic phenotypes of subclinical atherosclerosis, which may represent different stages of disease as well as common and distinct determinants. Methods— A total of 1515 middle-aged healthy white subjects (940 males and 575 females) were included. Common carotid artery intima-media thickness (CIMT) and presence of atherosclerotic plaques were assessed by B-mode ultrasound. Results— After adjustment for established risk factors, per 1 &mgr;g/mL decrease in adiponectin CIMT increased on the average by 3.48 &mgr;m in males (95% CI, 1.23 to 5.73 &mgr;m) and by 2.39 &mgr;m in females (95% CI, 0.50 to 4.27 &mgr;m). After dichotomizing adiponectin levels at the median and adjustment for established risk factors, the mean difference of CIMT between subjects with low and high adiponectin levels was 20.42 &mgr;m in men (95% CI, 6.80 to 34.04; P=0.003) and 20.75 &mgr;m in women (95% CI, 1.08 to 40.42; P=0.039). No significant relationship was found between adiponectin levels and presence of atherosclerotic plaques. Conclusion— Our results demonstrate an independent negative association of adiponectin levels and CIMT, whereas no relationship with presence of atherosclerotic plaques was found, thus suggesting hypoadiponectinemia as a risk factor in the development of early atherosclerosis.

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

BackgroundThere is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.MethodsThis study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease.ResultsHaplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046).ConclusionOur data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.

The adiponectin gene is associated with adiponectin levels but not with characteristics of the insulin resistance syndrome in healthy Caucasians

Low concentrations of adiponectin, the protein product of the APM1 gene, have been reported to be associated with obesity and insulin resistance. However, contrasting results have been described on the genetic variability in APM1 and characteristics of the metabolic syndrome and adiponectin serum concentrations. In the present study, we investigated the association of the two most well-known SNPs of APM1 (+45T>G and +276G>T) and their haplotypes, with serum adiponectin concentrations, metabolic parameters and intima-media thickness of the carotid arteries in 1745 well-phenotyped asymptomatic unrelated Caucasian subjects of the SAPHIR cohort. The common T-allele (88.5%) of SNP +45T>G and the common G-allele (70.5%) of SNP +276G>T were associated with significantly lower serum adiponectin levels (P=0.0008 and P=0.00005, respectively). The most frequent haplotype TG (59.0%) defined by both loci showed a strong association with lower serum adiponectin concentrations (P=0.000000002). A clear effect per copy of the respective haplotype was observed. This association was most pronounced in lean and insulin-sensitive subjects. The two less common haplotypes TT (29.5%) and GG (11.5%) were associated with higher serum adiponectin levels in a dose-dependent association. Interestingly, no significant association between the adiponectin 45–276 haplotypes and the majority of parameters of the metabolic syndrome or intima-media thickness of the carotid arteries was found in our study. In summary, we replicated a strong association of the adiponectin 45–276 genotypes and haplotypes with adiponectin levels in healthy Caucasians. However, we could not confirm an association of this gene locus with metabolic parameters of the insulin resistance syndrome.

Potentially inappropriate medication in geriatric patients: the Austrian consensus panel list

ZusammenfassungHINTERGRUND: Bei geriatrischen Patienten stellen inadäquate Medikamentenverordnungen einen wichtigen Risikofaktor für unerwünschte Arzneimittelereignisse dar. Sie führen in diesem Zusammenhang zu einer Zunahme von Spitalszuweisungen, welche die Gesundheitskosten belasten. Die Entwicklung Konsensus-basierter Listen von Medikamenten, die bei geriatrischen Patienten im Allgemeinen vermieden werden sollten, wird als eine mögliche Strategie angesehen, um die Qualität der medikamentösen Behandlung zu steigern. ZIEL: Erstellung einer, den österreichischen Verschreibungsgewohnheiten und der Marktsituation angepassten, Konsensus-basierten Liste von Arzneimitteln, deren Verordnung potentiell inadäquat für geriatrische Patienten ist, und die deshalb vermieden werden sollten. METHODE: Als Evaluierungsmethode wurde ein zwei-stufiger Delphi Prozess gewählt, an dem acht Experten mit Erfahrung in der medikamentösen Therapie geriatrischer Patienten teilnahmen. In der ersten Runde bewerteten die Experten Medikamente einer vorgegebenen Liste anhand einer 5-stufigen Likert Skala von sicher potentiell unangemessen bis sicher nicht potentiell unangemessen. Alle Medikamente, für deren Bewertung die obere Grenze des 95 % Konfidenzintervalls unter 3,0 lag, wurden als potentiell unangemessen klassifiziert. Medikamente, deren 95 % KI den Wert 3,0 umschloss, wurden in der zweiten Runde wieder anhand einer 5-stufigen Likert Skala bewertet, ebenso wie die in der ersten Runde neu vorgeschlagenen Medikamente. Nach Analyse der Ergebnisse der zweiten Runde wurde die finale Liste erstellt. RESULTATE: Von den vorgegebenen 102 Medikamenten wurden 61 Medikamente (59,2 %) bereits in der ersten Runde als potentiell unangemessen für ältere Menschen eingestuft. Sechs Medikamente, die in der zweiten Runde erneut evaluiert wurden, und sechs in der ersten Runde neu vorgeschlagene Medikamente wurden in der zweiten Runde als potentiell inadäquat klassifiziert. Die finale Liste enthält 73 Arzneimittel, die aufgrund eines ungünstigen Nutzen/Risiko Profils oder aufgrund fraglicher Wirksamkeit bei geriatrischen Patienten nicht verordnet werden sollten. SCHLUSSFOLGERUNG: Die Österreichische PIM Liste kann für klinisch tätige Ärzte ein in der Praxis anwendbares Instrument darstellen, das zu einer Verbesserung der Qualität von Medikamentenverordnungen bei älteren Patienten beiträgt. Studien zur Validierung der PIM-Liste stehen in Österreich ebenso wie in anderen Ländern mit bereits veröffentlichten PIM-Listen noch aus.SummaryBACKGROUND: The practice of inappropriate medication and drug prescription is a major risk factor for adverse drug reactions in geriatric patients and increases the individual, as well as overall, rates of hospital admissions, resulting in increased health care expenditures. A consensus-based list of drugs, generally to be avoided in geriatric patients, is a practical tool to possibly improve the quality of prescribing. OBJECTIVE: The aim was to develop a consensus-based list of potentially inappropriate medications (PIM) for geriatric patients in Austria. Local market characteristics and documented prescribing regimens were considered in detail. METHODS: A two-round Delphi process involving eight experts in the field of geriatric medicine was undertaken to create a list of potentially inappropriate medications. Using a 5-point Likert scale (from strong agreement to strong disagreement), mean ratings from the experts were evaluated for each drug selected in the first round. The participants were first asked to comment on the potential inappropriateness of a preliminary list of drugs, and to propose alternate substances missing in the previous questionnaire for a second rating process. All drugs whose upper limit of the 95% CI was less than 3.0 were classified as potentially inappropriate. Drugs with a 95% CI enclosing 3.0 entered a second rating by the experts, in addition to other substances suggested during the first questionnaire. Drugs in the second rating were evaluated in comparable fashion to the first one. The final list was synthesized from the results in both rounds. RESULTS: Out of a preliminary list of 102 drugs, 61 drugs (59.2%) were classified as potentially inappropriate for geriatric persons in the first Delphi- round. In the second rating, six drugs that were reevaluated, and six drugs proposed additionally, were rated as potentially inappropriate. The final list contains 73 drugs to be avoided in older patients because of an unfavorable benefit/risk profile and/or unproven effectiveness. The list also contains suggestions for therapeutic alternatives and information about pharmacological and pharmacokinetic characteristics of all drugs judged as potentially inappropriate. CONCLUSION: The current Austrian list of potentially inappropriate medications may be a helpful tool for clinicians to increase the quality of prescribing in older patients. Like all explicit lists previously published, its validity needs to be proven in validation studies.

Associations of the UCP2 Gene Locus With Asymptomatic Carotid Atherosclerosis in Middle-Aged Women

Objective—Reactive oxygen species (ROS) contribute to atherogenesis. Uncoupling protein 2 (UCP2) reduces mitochondrial ROS generation and protects against the disease in animal models. A common −866G/A promoter polymorphism that has been associated with obesity and &bgr;-cell function may also affect UCP2 gene expression in cells of the arterial wall. Methods and Results—Genotype distributions of the −866G/A and of a 45nt-del/ins polymorphism in the 3′-untranslated region of the UCP2 gene were determined in 1334 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). We observed a modest association of the −866G/A promoter polymorphism and 2-loci haplotypes with asymptomatic carotid atherosclerosis in female study participants. Functional studies revealed increased expression of the −866G wild-type allele in human umbilical vein endothelial cells and differentiated THP-1 cells. Electrophoretic mobility shift assay studies and antibody-interference assays performed with nuclear extracts of various cell lines showed binding of cell-type specific protein complexes to the region encompassing the −866 site and suggested involvement of hypoxia inducible factor 1&agr; in the regulation of UCP2 gene expression in endothelial cells and macrophages. Conclusions—Our results suggest a role of UCP2 in atherogenesis as originally proposed from studies in animal and cell culture models.

Associations of a Human G Protein β3 Subunit Dimorphism With Insulin Resistance and Carotid Atherosclerosis

Background and Purpose— The C825T dimorphism of the gene encoding the human G protein &bgr;3 subunit (GNB3) is associated with hypertension and obesity. Although these findings suggest an association with insulin resistance and atherosclerosis, this hypothesis has yet been tested only partially. Methods— To investigate this hypothesis, the C825T dimorphism was determined in a population of 932 middle-aged white subjects of middle European (Austrian) origin. Insulin sensitivity was measured with the short insulin tolerance test; intima-media thickness of the carotid artery and morphological plaque burden were measured by ultrasound. Results— Insulin sensitivity was found to be significantly lower in carriers of the T allele (3.55±1.27 versus 3.92±1.30%/min, P =0.012) in the group of male subjects with abdominal body fat distribution (waist-to-hip ratio >0.9). No effect was observed in women or men with a waist-to-hip ratio <0.9. Advanced carotid artery plaques were more frequent (odds ratio, 1.606; 95% confidence interval, 1.002 to 2.575;P =0.04) in carriers of the T allele regardless of sex. No effect was observed with regard to carotid artery intima-media thickness. Conclusions— In summary, our results demonstrate that the GNB3 825T allele is associated with reduced insulin sensitivity in men with abdominal fat distribution and with more advanced carotid atherosclerosis in middle-aged white men and women.

Peroxisome Proliferator–Activated Receptor-γ Coactivator-1 Gene Locus: Associations with Hypertension in Middle-Aged Men

Abstract—Peroxisome proliferator–activated receptor-&ggr; coactivator-1 (PPARGC1/PGC-1) is a transcriptional coactivator of nuclear hormone receptors implicated in blood pressure regulation. We therefore ascertained whether the PPARGC1 gene locus is associated with hypertension. We studied associations of 3 polymorphisms in PPARGC1 transcripts with hypertension in 683 middle-aged men and 530 middle-aged women of a cross-sectional Austrian population. Hypertension was defined by average values of systolic or diastolic ambulatory blood pressure readings (taken between 7 am and 10 pm) above 140 and/or 90 and/or use of antihypertensive medication. Among the 3 polymorphic sites, genotype distributions associated with Gly482Ser differed by hypertension status in men (P =0.0038), but not in women. The less common Ser482 allele was associated with a modest, but significant, reduction in the prevalence of hypertension in men. The distribution of 3 loci haplotypes also differed in men with and without hypertension (P =0.015). Despite its moderate effect, but because of its high frequency (≈64%), the more common risk allele contributed to hypertension in 35% (95% CI 16% to 54%) of our male population. These results suggest, but do not prove, that PPARGC1 participates in blood pressure control, and sequence substitutions at its gene locus confer an increased risk of hypertension to a substantial proportion of men.

Are plasma VEGF and its soluble receptor sFlt-1 atherogenic risk factors? Cross-sectional data from the SAPHIR study.

AIMSnVascular endothelial growth factor (VEGF) is a potent hypoxia-regulated angiogenic factor. Its soluble receptor soluble (s)Flt-1 binds VEGF with high affinity inhibiting the angiogenic function of VEGF. The role of circulating VEGF in atherosclerosis is unclear.nnnMETHODS AND RESULTSnIn 909 healthy subjects (511 male, 398 female) from the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) we determined fasting plasma VEGF and sFlt-1 concentration, cardiovascular risk factors and carotid atherosclerosis. VEGF levels were lower and sFlt-1 levels higher in men than in women. VEGF and sFlt-1 showed a positive correlation. In the entire population VEGF correlated positively with age, BMI, insulin resistance, white blood cell and platelet count, C-reactive protein (CRP) and carotid intima media thickness (IMT). After adjustment for age, VEGF showed a weak positive correlation with BMI, liver enzymes, CRP and platelet count in males. In females VEGF correlated negatively with LDL-cholesterol and positively with insulin resistance and platelet count. After adjustment for age, no significant correlation with carotid atherosclerosis could be detected.nnnCONCLUSIONnPlasma VEGF and sFlt-1 are only weakly correlated with cardiovascular risk factors, suggesting that circulating VEGF levels do have only a minor impact on the development of atherosclerosis.

The Mitochondrial T16189C Polymorphism Is Associated with Coronary Artery Disease in Middle European Populations

Background The pivotal role of mitochondria in energy production and free radical generation suggests that the mitochondrial genome could have an important influence on the expression of multifactorial age related diseases. Substitution of T to C at nucleotide position 16189 in the hypervariable D-loop of the control region (CR) of mitochondrial DNA (mtDNA) has attracted research interest because of its suspected association with various multifactorial diseases. The aim of the present study was to compare the frequency of this polymorphism in the CR of mtDNA in patients with coronary artery disease (CAD, nu200a=u200a482) and type 2 diabetes mellitus (T2DM, nu200a=u200a505) from two study centers, with healthy individuals (nu200a=u200a1481) of Middle European descent in Austria. Methodology and Principal Findings CR polymorphisms and the nine major European haplogroups were identified by DNA sequencing and primer extension analysis, respectively. Frequencies and Odds Ratios for the association between cases and controls were calculated. Compared to healthy controls, the prevalence of T16189C was significantly higher in patients with CAD (11.8% vs 21.6%), as well as in patients with T2DM (11.8% vs 19.4%). The association of CAD, but not the one of T2DM, with T16189C remained highly significant after correction for age, sex and body mass index (BMI) and was independent of the two study centers. Conclusions and Significance Our results show for the first time a significant association of T16189C with CAD in a Middle European population. As reported in other studies, in patients with T2DM an association with T16189C in individuals of European decent remains questionable.