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author:("mellin, T")
1.  Copeptin in patients with heart failure and preserved ejection fraction: a report from the prospective KaRen-study 
Open Heart  2015;2(1):e000260.
Underlying mechanisms of heart failure (HF) with preserved ejection fraction (HFPEF) remain unknown. We explored copeptin, a biomarker of the arginine vasopressin system, hypothesising that copeptin in HFPEF is elevated, associated with diastolic dysfunction and N-terminal pro-brain natriuretic peptide (NT-proBNP) and predictive of HF hospitalisation and mortality.
Methods and analysis
In a prospective observational substudy of the The Karolinska Rennes (KaRen) 86 patients with symptoms of acute HF and ejection fraction (EF) ≥45% were enrolled. After 4–8 weeks, blood sampling and echocardiography was performed. Plasma-copeptin was analysed in 86 patients and 62 healthy controls. Patients were followed in median 579 days (quartile 1; quartile 3 (Q1;Q3) 276;1178) regarding the composite end point all-cause mortality or HF hospitalisation.
Ethics and dissemination
The patients with HFPEF had higher copeptin levels, median 13.56 pmol/L (Q1;Q3 8.56;20.55) than controls 5.98 pmol/L (4.15;9.42; p<0.001). Diastolic dysfunction, assessable in 75/86 patients, was present in 45 and absent in 30 patients. Copeptin did not differ regarding diastolic dysfunction and did not correlate with cardiac function but with NT-proBNP (r=0.223; p value=0.040). In univariate Cox regression analysis log copeptin predicted the composite end point (HR 1.56 (95% CI 1.03 to 2.38; p value=0.037)) but not after adjusting for NT-proBNP (HR 1.39 (95% CI 0.91 to 2.12; p value=0.125)).
In the present patients with HFPEF, copeptin is elevated, correlates with NT-proBNP but not markers of diastolic dysfunction, and has prognostic implications, however blunted after adjustment for NT-proBNP. The HFPEF pathophysiology may be better reflected by markers of neurohormonal activation than by diastolic dysfunction.
Trial registration number NCT00774709.
PMCID: PMC4636678  PMID: 26568833
2.  Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology 
In order to influence every day clinical practice professional organisations issue management guidelines. Cross-sectional surveys are used to evaluate the implementation of such guidelines. The present survey investigated screening for glucose perturbations in people with coronary artery disease and compared patients with known and newly detected type 2 diabetes with those without diabetes in terms of their life-style and pharmacological risk factor management in relation to contemporary European guidelines.
A total of 6187 patients (18–80 years) with coronary artery disease and known glycaemic status based on a self reported history of diabetes (previously known diabetes) or the results of an oral glucose tolerance test and HbA1c (no diabetes or newly diagnosed diabetes) were investigated in EUROASPIRE IV including patients in 24 European countries 2012–2013. The patients were interviewed and investigated in order to enable a comparison between their actual risk factor control with that recommended in current European management guidelines and the outcome in previously conducted surveys.
A total of 2846 (46 %) patients had no diabetes, 1158 (19 %) newly diagnosed diabetes and 2183 (35 %) previously known diabetes. The combined use of all four cardioprotective drugs in these groups was 53, 55 and 60 %, respectively. A blood pressure target of <140/90 mmHg was achieved in 68, 61, 54 % and a LDL-cholesterol target of <1.8 mmol/L in 16, 18 and 28 %. Patients with newly diagnosed and previously known diabetes reached an HbA1c <7.0 % (53 mmol/mol) in 95 and 53 % and 11 % of those with previously known diabetes had an HbA1c >9.0 % (>75 mmol/mol). Of the patients with diabetes 69 % reported on low physical activity. The proportion of patients participating in cardiac rehabilitation programmes was low (≈40 %) and only 27 % of those with diabetes had attended diabetes schools. Compared with data from previous surveys the use of cardioprotective drugs had increased and more patients were achieving the risk factor treatment targets.
Despite advances in patient management there is further potential to improve both the detection and management of patients with diabetes and coronary artery disease.
PMCID: PMC4591740  PMID: 26427624
Coronary artery disease; Type 2 diabetes; Secondary prevention; Management; Guideline adherence; Blood lipids; Blood pressure; Glycaemic control
3.  Detection of Circulating hcmv-miR-UL112-3p in Patients with Glioblastoma, Rheumatoid Arthritis, Diabetes Mellitus and Healthy Controls 
PLoS ONE  2014;9(12):e113740.
microRNAs (miRNA) are 18–22 nucleotides long non-coding RNAs that regulate gene expression at a post-transcriptional level. Human cytomegalovirus (HCMV) encodes at least 26 known mature miRNAs. hcmv-miR-UL112-3p (miR-UL112-3p) is the most well characterized HCMV miRNA, which is suggested to play role in establishment and maintenance of viral latency. Elevated miR-UL112-3p levels have been reported to be present in plasma of patients with hypertension.
In this study, we aimed to quantify miR-UL112-3p levels in the plasma/serum of patients with Diabetes Mellitus (DM; from the DIGAMI-2 cohort), Glioblastoma multiforme (GBM), Rheumatoid Arthritis (RA) and Healthy Controls (HC).
Study Design
Total RNA was isolated from plasma/serum samples of 87 patients and controls, a TaqMan miRNA assay was performed to detect miR-UL112-3p and the copy numbers were normalized to 10 ng of total RNA. HCMV IgG and IgM were analysed using ELISA.
HCMV miR-UL112-3p was detected in 14/27 (52%) of DM, 5/20 (25%) of GBM, 1/20 (5%) of RA patients and in 2/20 (10%) of HC, respectively. Anti-HCMV IgG was detected in 85%, 65%, 75% of patients and 70% of HC, respectively. Anti-HCMV IgM was found only in one GBM patient of 87 examined patients and controls.
A higher prevalence of miR-UL112-3p was detected in DM and GBM patients than in RA patients and HC. Elevated levels of miR-UL112-3p and higher prevalence of HCMV IgG were observed in DM patients. Whether the presence of circulating miR-UL112-3p denotes a biomarker of HCMV latency or active replication in patients warrants further investigation.
PMCID: PMC4252052  PMID: 25462570
4.  Complement Activation and Prognosis in Patients With Type 2 Diabetes and Myocardial Infarction 
Diabetes Care  2012;35(4):911-917.
The activation of the complement system may be involved in the pathology of myocardial infarction (MI) and type 2 diabetes. To explore their potential as prognostic markers, we characterized two factors in the complement cascade, the end product sC5b-9 and the mannose-binding lectin–associated Ser protease-2 (MASP-2), in type 2 diabetic patients with suspected MI.
Plasma sC5b-9 and MASP-2 were determined in patients with MI and type 2 diabetes (n = 397; median age 70; male 68%). The adjudicated end points were cardiovascular events (CVEs), including cardiovascular mortality and nonfatal MI or stroke.
The median sC5b-9 was 134 μg/L (interquartile range [IQR] 101–190 μg/L) and the median MASP-2 was 333 μg/L (IQR 235–463 μg/L), with no significant correlation between them. Women had higher sC5b-9 than men (median 152 vs. 130 μg/L; P = 0.02). Both sC5b-9 and MASP-2 were correlated to age and creatinine clearance, while MASP-2 was also correlated to BMI. During a median follow-up of 2.4 years, CVEs occurred in 141 patients (36%). Both sC5b-9 (hazard ratio 1.37 [95% CI 1.13–1.65]; P < 0.01) and MASP-2 (0.68 [0.51–0.92]; P = 0.01) predicted CVEs in unadjusted analyses. After multiple adjustments, the predictive capacity remained for sC5b-9 (1.30 [1.02–1.66]; P = 0.04) but not for MASP-2.
In type 2 diabetic patients with MI, high levels of sC5b-9 predict future CVE. This indicates that the complement system may play a significant role in the pathology of the subsequent myocardial damage and that the pathways leading to complement activation warrant further exploration as potential therapeutic targets to improve the prognosis for these patients.
PMCID: PMC3308270  PMID: 22357179
5.  Mannose-Binding Lectin Genotype and Phenotype in Patients With Type 2 Diabetes and Myocardial Infarction 
Diabetes Care  2010;33(11):2451-2456.
The present study characterizes mannose-binding lectin (MBL), an activator of the complement system and thereby important for inflammatory activation, in patients with diabetes and myocardial infarction.
Serum (S)-MBL was determined at hospital admission in 387 patients with type 2 diabetes (median age 70 years; 68% male) with myocardial infarction, and genotyping was performed in 287 patients. Cardiovascular events (cardiovascular mortality and nonfatal myocardial infarction or stroke) were recorded during 2.5 years.
Median S-MBL was 1,212 μg/l (interquartile range [IQR] 346–2,681 μg/l). Of the subjects, 54% in the geno- and phenotype subgroup had a high-coding MBL genotype (median S-MBL = 2,658 μg/l [IQR 1,715–3,829]) and 46% a low-coding MBL genotype (373 μg/l [100–765]). S-MBL did not correlate with age, BMI, creatinine clearance, glucose, or A1C. Cardiovascular events occurred in 136 (35%) patients. S-MBL did not predict events in univariable analyses (hazard ratio 0.93 [95% CI 0.85–1.01]; P = 0.09). In unadjusted analyses, the risk of events was lower in patients with a high genotype and S-MBL above the median for their genotype (0.49 [0.26–0.92]; P = 0.026) than for patients with a low genotype and S-MBL below the median for their genotype. The prediction capacity of the geno- and phenotype model was of borderline significance in adjusted Cox regression.
Patients with type 2 diabetes and myocardial infarction have MBL genotypes that are similar to those known in the general population. The combination of a low-coding MBL genotype with a low S-MBL appears to be prognostically unfavorable, but the association is blunted by traditional risk markers.
PMCID: PMC2963511  PMID: 20693349
6.  Copeptin, IGFBP-1, and Cardiovascular Prognosis in Patients With Type 2 Diabetes and Acute Myocardial Infarction 
Diabetes Care  2010;33(7):1604-1606.
To determine whether C-terminal provasopressin (copeptin) explains the prognostic importance of insulin growth factor binding protein-1 (IGFBP-1) in patients with myocardial infarction and type 2 diabetes.
Copeptin and IGFBP-1 were analyzed in 393 patients participating in the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial.
Copeptin was associated with IGFBP-1 (Spearman rank correlation test, r = 0.53; P < 0.001). During follow-up there were 138 cardiovascular events (cardiovascular death, myocardial infarction, and stroke). In univariate Cox proportional hazard regression analyses both biomarkers were predictors of events: the hazard ratio for log copeptin was 1.59 (95% CI 1.41–1.81; P < 0.001) and for log IGFBP-1 was 1.49 (1.26–1.77; P < 0.001). In the final model, adjusting for age and renal function, copeptin was the only independent predictor (1.35 [1.16–1.57]; P < 0.001).
Copeptin is an independent predictor of cardiovascular events and appears to at least partly explain the prognostic impact of IGFBP-1 in patients with type 2 diabetes and myocardial infarction. Copeptin may be a pathogenic factor to address to improve outcome in these patients.
PMCID: PMC2890367  PMID: 20413521
7.  Relationship of weight gain in infancy to subcutaneous fat and relative weight at 10 1/2 years of age. 
In a representative sample of 895 schoolchildren, aged between 9 years 10 months and 11 years 2 months, the risk of being overweight or obese was compared between those who had gained weight rapidly during infancy and those whose weight gain had been normal. A substantially increased risk ratio was found only in boys for whom a correlation analysis showed that the total weight gain during the first year of life was associated with the total body mass in relation to height, more or less independently of the degree of fatness at 10 1/2 years of age. In girls, a direct but very weak association was found between weight gain in infancy and the degree of fatness at 10 1/2 years. The implications of these findings with respect to aetiology and the possibilities of prevention are briefly discussed.
PMCID: PMC478973  PMID: 1009275
8.  Weight gain in infancy and physical development between 7 and 10 1/2 years of age. 
Heights and weights were measured in 963 10-year-old children, whose weight data from the first year of life were available. Rapid weight gain in infancy was arbitrarily defined on the basis of sex-specific percentiles of weight gain at four-month intervals and from birth to 12 months. In girls, no significant association between rapid weight gain in infancy and overweight at 10 1/2 years was found. In boys, the association was significant for severe overweight (greater than 120% of standard weight for height). An estimation of the possible benefit of an intervention programme (food restriction in all male infants with rapid weight gain) showed, however, that at the very best 12% of the boys treated in this way could be expected to gain some benefit. The result of a correlation analysis between weight gain in infancy and change in height and relative weight between 7 and 10 1/2 years suggested that the factors which determined weight gain in infancy were no longer operative at ages between 7 and 10 1/2 years.
PMCID: PMC478972  PMID: 1009274

Results 1-9 (9)