Elevated levels of serum PCSK9 in male patients with symptomatic peripheral artery disease: The CAVASIC study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) affects more than 200 million people worldwide. Increased low-density lipoprotein cholesterol (LDL-C)levels are a risk factor for PAD and the concentrations are influenced by proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates the recycling of the LDL receptors to the cell membrane surface. Only a limited number of mostly small studies investigated the association between serum PCSK9 concentrations and PAD of different definition, which revealed contrasting results. METHODS: Serum PCSK9, lipoprotein(a) [Lp(a)] and other lipoprotein concentrations were measured in male participants of the CAVASIC study, a case-control study of 248 patients with intermittent claudication and 251 age and diabetes-matched controls. RESULTS: PAD patients had significantly higher PCSK9 concentrations when compared to controls (250 ± 77 vs. 222 ± 68 ng/mL, p < 0.001). Logistic regression analysis with adjustment for age revealed that an increase in PCSK9 concentrations of 100 ng/mL was associated with a 1.78-fold higher risk for PAD (95%CI 1.38-2.33, p = 1.43 × 10-5). The association attenuated, but was still significant when adjusting additionally for age, Lp(a)-corrected LDL cholesterol, HDL cholesterol, high-sensitivity-CRP, statin treatment, hypertension, diabetes mellitus and smoking (OR = 1.49, 95%CI 1.03-2.18, p = 0.035). The strongest association was observed when both PCSK9 concentrations were above the median and Lp(a) concentrations were above 30 mg/dL (OR = 3.35, 95%CI 1.49-7.71, p = 0.0038). CONCLUSIONS: Our findings suggest an association of higher PCSK9 concentrations with PAD, which was independent of other lipid parameters and classical cardiovascular risk factors.

The fate of patients with intermittent claudication in the 21st century revisited - results from the CAVASIC Study.

Patients with intermittent claudication carry a high risk for cardiovascular complications. The TransAtlantic Inter-Society Consensus (TASC) Group estimated a five-year overall mortality of 30% for these patients, the majority dying from cardiovascular causes. We investigated whether this evaluation is still applicable in nowadays patients. We therefore prospectively followed 255 male patients with intermittent claudication from the CAVASIC Study during 7 years for overall mortality, vascular morbidity and mortality and local PAD outcomes. Overall mortality reached 16.1% (n = 41). Most patients died from cancer (n = 20). Half of patients (n = 22; 8.6%) died within the first five years. Incident cardiovascular events were observed among 70 patients (27.5%), 54 (21.2%) during the first five years. Vascular mortality was low with 5.1% (n = 13) for the entire and 3.1% for the first five years of follow-up. Prevalent coronary artery disease did not increase the risk to die from all or vascular causes. PAD symptoms remained stable or improved in the majority of patients (67%). In summary, compared to TASC, the proportion of cardiovascular events did not markedly decrease over the last two decades. Vascular mortality, however, was low among our population. This indicates that nowadays patients more often survive cardiovascular events and a major number dies from cancer.

[Type 2 Diabetes mellitus-screening and prevention: Update 2016]. / Typ 2 Diabetes mellitus - Screening und Prävention : Update 2016.

The prevalence of diabetes is increasing in westernized countries. In addition, about half of all patients suffering from diabetes are not diagnosed. The current article represents the recommendations of the Austrian Diabetes Association for the screening and prevention of type 2 diabetes, based on currently available evidence.

Serum concentrations of L-arginine and L-homoarginine in male patients with intermittent claudication: a cross-sectional and prospective investigation in the CAVASIC Study.

BACKGROUND: High serum concentrations of l-arginine and l-homoarginine increase nitric oxide (NO) availability and thereby improve endothelial function. Information about the association of these markers with peripheral arterial disease (PAD) and related outcomes is sparse. METHODS: l-arginine, its metabolites and l-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes-matched controls. After the baseline investigation PAD patients were prospectively followed (median 7 years). The association of these markers with symptomatic PAD at baseline, incident cardiovascular events and all-cause mortality was assessed. RESULTS: At baseline each increase of ln-l-homoarginine and l-arginine by one standard deviation was associated with symptomatic PAD: OR=0.75, 95%CI 0.59-0.96, P=0.02 and OR=1.36, 95%CI 1.07-1.73, P=0.01, respectively (both models adjusted for ln-CRP, GFR, HDL cholesterol, and current smoking). Only l-arginine remained significant after additional adjustment for ln-NT-proBNP and hs-cTnT: OR=1.49, P=0.002. In the Cox regression analysis elevated ln-l-homoarginine significantly reduced the risk to die (n=38) even independent from ln-NT-proBNP and hs-cTnT: HR=0.59, 95%CI 0.41-0.84, P=0.004. l-arginine was significantly predicting incident cardiovascular events (n=65): HR=1.68, 95%CI 1.35-2.10, P < 0.001. CONCLUSIONS: This study in male patients with intermittent claudication and age- and diabetes-matched controls showed an association of l-homoarginine and l-arginine with PAD. During follow-up, l-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity. l-homoarginine was related to all-cause mortality implying a broader role in metabolic processes besides endothelial function.

Effects of smoking cessation on ß-cell function, insulin sensitivity, body weight, and appetite.

OBJECTIVE: To stop smoking is commonly associated with significant weight gain, but the mechanisms for this are poorly understood. We assessed the effects of smoking cessation on body weight, insulin sensitivity, ß-cell function, and appetite. SUBJECTS AND METHODS: Twenty-seven long-term smokers (n=27; nine females/18 males, 28±1 years, 22.9±0.6 kg/m(2)) attending an ambulatory smoking cessation program in a community hospital in Vienna, Austria were examined at baseline (Visit A; still smoking) and after a minimum of 3 months of smoking abstinence (Visit B; n=14); relapsed smokers were not followed up. Participants underwent 3-h oral glucose tolerance tests and body composition measurements at each study visit. Fasting (QUICKI) and dynamic (oral glucose insulin sensitivity (OGIS)) insulin sensitivity and ß-cell secretion (insulinogenic index 140 (IGI40)) were calculated. Food intake was quantified with a free choice buffet. Fasting plasma concentrations of neuropeptide-Y (NPY), peptide-YY (PYY), glucagon-like peptide 1 (GLP1), leptin, ghrelin, and visfatin were measured. RESULTS: AFTER 3 MONTHS' SMOKING ABSTINENCE, BODY WEIGHT, AND FAT MASS WERE INCREASED (+4 AND +22% RESPECTIVELY, P0.05) AND FASTING INSULIN SENSITIVITY DETERIORATED (QUICKI: post, 0.37±0.02 vs baseline, 0.41±0.2; P<0.05), while OGIS remained unchanged throughout. IGI40 increased by 31% after >3 months' smoking abstinence (P<0.01). Carbohydrate ingestion increased after stopping smoking (P<0.05). NPY fasting levels were increased after >3 months (P<0.05), PYY, GLP1, leptin, ghrelin, and visfatin were unchanged. CONCLUSION: Smoking cessation is associated with transient metabolic changes including increased ß-cell secretion in response to glucose and fasting insulin resistance. These alterations may be associated with or contribute to the body weight gain after smoking cessation.

The association of relative telomere length with symptomatic peripheral arterial disease: results from the CAVASIC study.

BACKGROUND AND OBJECTIVES: Short telomere length has been described to be associated with biological aging including atherosclerosis phenotypes. However, information in patients with symptomatic peripheral arterial disease (PAD) is sparse. We therefore aimed to investigate whether inter-individual differences in relative telomere length (RTL) are associated with symptomatic PAD. DESIGN: We measured RTL by a quantitative PCR method in the CAVASIC Study, a cohort of 241 male Caucasian patients diagnosed with intermittent claudication and 249 age- and diabetes-matched controls. RESULTS: We observed significantly shorter mean RTL in patients than in controls (1.24 ± 0.19 vs. 1.32 ± 0.23, p < 0.001). Each shortening of RTL by one standard deviation significantly increased the odds for PAD by 44%: age-adjusted OR = 1.44 (95%CI 1.19-1.75, p < 0.001). This association remained significant after additional adjustment for log-C-reactive protein, glomerular filtration rate, HDL cholesterol, current smoking and log N-terminal pro-B-type natriuretic peptide (NT-proBNP). Excluding patients with prevalent cardiovascular disease revealed very similar results. When we compared the model fit of the various adjustment models including cardiac risk factors and/or NT-proBNP the addition of RTL significantly improved discrimination between patients and controls. CONCLUSION: This study in a male cohort of patients with intermittent claudication and age- and diabetes-matched controls indicates a significant association of shorter relative telomere length with PAD. Our results reinforce RTL as a marker for PAD that reflects the influence of genetic and environmental risk factors. Moreover, the association remains significant after excluding patients and controls free from prevalent cardiovascular disease.

Comparison and evaluation of cardiac biomarkers in patients with intermittent claudication: results from the CAVASIC study.

BACKGROUND: Plasma concentrations of the peptides midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), and C-terminal endothelin-1 precursor fragment (CT-proET-1) are increased in various cardiovascular conditions. However, there is limited information about the association and comparative performance of these peptides in peripheral arterial disease (PAD). METHODS: The associations of MR-proADM, MR-proANP, and CT-proET-1 plasma concentrations with symptomatic PAD were investigated in the CAVASIC (Cardiovascular Disease in Intermittent Claudication) Study. Study participants were a male cohort of 238 patients with a diagnosis of intermittent claudication (IC) and 245 age- and diabetes-matched controls. Results were compared to those for N-terminal pro-B-type natriuretic peptide (NT-proBNP). RESULTS: Each increase of MR-proADM, MR-proANP, and CT-proET-1 by 1 SD was significantly associated with symptomatic PAD: odds ratio (OR) = 1.78 (95% CI, 1.41-2.25, P < 0.001), OR = 1.32 (95% CI, 1.06-1.66, P = 0.014), and OR = 1.80 (95% CI, 1.43-2.28, P < 0.001), respectively. The association remained significant for all 3 markers after additional adjustment for log C-reactive protein, serum creatinine, HDL cholesterol, and current smoking. When one adjusts for log NT-proBNP and excluding individuals with prevalent cardiovascular disease, MR-proADM and CT-proET-1 still predicted symptomatic PAD. Extended adjustment models including MR-proADM or CT-proET-1 showed significantly improved model fits compared to models including classical cardiac risk factors or NT-proBNP and led to significant reclassification (P < 0.05). CONCLUSIONS: This study in a male cohort of patients with IC and age- and diabetes-matched controls indicates a significant association of high MR-proADM, MR-proANP, and CT-proET-1 concentrations with PAD. MR-proADM and CT-proET-1 provide additive information in comparison to NT-proBNP. Moreover, MR-proADM and CT-proET-1 significantly predict PAD in those patients and controls free from prevalent CVD.

[Type 2 diabetes mellitus-screening and prevention]. / Typ 2 Diabetes Mellitus - Screening und Prävention.

The prevalence of diabetes is increasing in westernized countries. In addition, about half of all patients suffering from diabetes are not diagnosed. The current article represents the recommendations of the Austrian Diabetes Association for the screening and prevention of type 2 diabetes, based on currently available evidence.

Alterations in gastrointestinal, endocrine, and metabolic processes after bariatric Roux-en-Y gastric bypass surgery.

OBJECTIVE: Obesity leads to severe long-term complications and reduced life expectancy. Roux-en-Y gastric bypass (RYGB) surgery induces excessive and continuous weight loss in (morbid) obesity, although it causes several abnormal anatomical and physiological conditions. RESEARCH DESIGN AND METHODS: To distinctively unveil effects of RYGB surgery on ß-cell function and glucose turnover in skeletal muscle, liver, and gut, nondiabetic, morbidly obese patients were studied before (pre-OP, five female/one male, BMI: 49 ± 3 kg/m(2), 43 ± 2 years of age) and 7 ± 1 months after (post-OP, BMI: 37 ± 3 kg/m(2)) RYGB surgery, compared with matching obese (CON(ob), five female/one male, BMI: 34 ± 1 kg/m(2), 48 ± 3 years of age) and lean controls (CON(lean), five female/one male, BMI: 22 ± 0 kg/m(2), 42 ± 2 years of age). Oral glucose tolerance tests (OGTTs), hyperinsulinemic-isoglycemic clamp tests, and mechanistic mathematical modeling allowed determination of whole-body insulin sensitivity (M/I), OGTT and clamp test ß-cell function, and gastrointestinal glucose absorption. RESULTS: Post-OP lost (P < 0.0001) 35 ± 3 kg body weight. M/I increased after RYGB, becoming comparable to CON(ob), but remaining markedly lower than CON(lean) (P < 0.05). M/I tightly correlated (τ = -0.611, P < 0.0001) with fat mass. During OGTT, post-OP showed ≥15% reduced plasma glucose from 120 to 180 min (≤4.5 mmol/L), and 29-fold elevated active glucagon-like peptide-1 (GLP-1) dynamic areas under the curve, which tightly correlated (r = 0.837, P < 0.001) with 84% increased ß-cell secretion. Insulinogenic index (0-30 min) in post-OP was ≥29% greater (P < 0.04). At fasting, post-OP showed approximately halved insulin secretion (P < 0.05 vs. pre-OP). Insulin-stimulated insulin secretion in post-OP was 52% higher than before surgery, but 1-2 pmol/min(2) lower than in CON(ob)/CON(lean) (P < 0.05). Gastrointestinal glucose absorption was comparable in pre-OP and post-OP, but 9-26% lower from 40 to 90 min in post-OP than in CON(ob)/CON(lean) (P < 0.04). CONCLUSIONS: RYGB surgery leads to decreased plasma glucose concentrations in the third OGTT hour and exaggerated ß-cell function, for which increased GLP-1 release seems responsible, whereas gastrointestinal glucose absorption remains unchanged but lower than in matching controls.

Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.

BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance. RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (ß=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (ß=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

Effects of gastric bypass surgery on insulin resistance and insulin secretion in nondiabetic obese patients.

Roux-en-Y-Gastric-Bypass (RYGB) reduces overall and diabetes-specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time-courses of glucose, insulin, C-peptide, and the incretin glucagon like peptide-1 (GLP-1) following an oral glucose load. Insulin-sensitivity was measured by a hyperinsulinemic-isoglycemic-clamp-test; glucose-turnover was determined using D-[6,6-(2)H(2)] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m(2)) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m(2)), in a lean (CON: BMI: 22.6 ± 0.6 kg/m(2)) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m(2)). RYGB reduced fasting plasma concentrations of insulin and C-peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C-peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic-area under the curve (Dyn-AUC): 0-90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP-1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin-stimulated glucose uptake tended to increase postoperatively (M-value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper-secretion of insulin and C-peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.

Association between the UGT1A1 TA-repeat polymorphism and bilirubin concentration in patients with intermittent claudication: results from the CAVASIC study.

BACKGROUND: Bilirubin has antioxidative and cytoprotective properties. Low plasma concentrations of bilirubin are reportedly associated with the development of coronary and cerebrovascular disease, and bilirubin concentrations are strongly correlated with the enzyme activity of the hepatic uridine diphosphate glucuronosyltransferase (UGT1A1). The activity of UGT1A1 is influenced by a TA-repeat polymorphism in the promoter of the UGT1A1 gene (UDP glucuronosyltransferase 1 family, polypeptide A1). In a case-control study, we investigated the association between the UGT1A1 polymorphism, bilirubin concentration, and intermittent claudication. METHODS: We included 255 consecutive male patients presenting with intermittent claudication in the investigation and matched the patients by age and diabetes mellitus with 255 control individuals. RESULTS: Plasma bilirubin concentrations were significantly lower in patients than in controls [mean (SD), 12.5 (5.3) micromol/L vs 15.4 (7.9) micromol/L; P < 0.001]. We found a clear association between the number of TA repeats and plasma bilirubin concentration. Considering the 6/6 TA-repeat genotype as the wild type, we observed a slight increase in bilirubin concentration individuals with the heterozygous 6/7 genotype and pronounced increases for those with the homozygous 7/7 genotype. This association occurred in both controls and patients; however, patients and controls were not significantly different with respect to UGT1A1 TA-repeat genotype frequencies. CONCLUSIONS: Our study of a well-phenotyped group of patients with intermittent claudication and control individuals revealed a clear association between low bilirubin concentrations and peripheral arterial disease but no association between the UGT1A1 polymorphism and the disease.

Increased plasma amylin in type 1 diabetic patients after kidney and pancreas transplantation: A sign of impaired beta-cell function?

OBJECTIVE: In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones. RESEARCH DESIGN AND METHODS: Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS: PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P < 0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P < 0.004). CONCLUSIONS: After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT.

[Type 2 diabetes mellitus--screening and prevention]. / Typ 2 Diabetes mellitus--Screening und Prävention.

The prevalence of diabetes is increasing in westernized countries. In addition, about half of all patients suffering from diabetes are not diagnosed. The current article represents the recommendations of the Austrian Diabetes Association for the screening and prevention of type 2 diabetes, based on currently available evidence.