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1.  Effects of omega 3 supplementation in elderly patients with acute myocardial infarction: design of a prospective randomized placebo controlled study 
BMC Geriatrics  2014;14:74.
Background
Both epidemiological and randomized clinical studies suggest that supplementation with very-long-chain marine polyunsaturated n-3 fatty acids (n-3 PUFA) have cardioprotective effects, however these results are not without controversy. Study population, sample-size, type of supplementation and type of endpoint have all varied widely accross different studies.
Therefore, the aims of the present study are to evaluate the effect of 2 years supplementation with capsules of very-long chain marine n-3 PUFA on top of standard therapy in elderly patients after acute myocardial infarction (AMI).
In addition, special characteristics of this population with regard to prediction of clinical outcome will be investigated. The hypothesis is that this supplementation on top of modern therapy will reduce the occurence of major cardiovascular events (MACE). We present the design of the OMEMI (OMega-3 fatty acids in Elderly patients with Myocardial Infarction) study.
Methods/Design
The OMEMI study is designed as a randomized, placebo-controlled double-blind multicenter trial.
Included are patients ≥70-82 years of age who have sustained AMI. Patients of either gender are eligible. Sample size calculation based on existing literature has resulted in the need for 1400 patients followed for 2 years, based on the assumption that the n-3 PUFA supplementation will reduce MACE with 30%. The study medication is Pikasol® Axellus AS, Norway, 3 capsules (1.8 g eicosapentaenoic acid (EPA) + docohexaenoic acid (DHA)) per day, and matching placebo is corn oil. The Primary end-point is the composite of total mortality, first non-fatal recurring AMI, stroke and revascularization. Secondary end-point is the occurrence of new onset atrial fibrillation. Extensive biobanking will be performed, including adipose tissue biopsies. Compliance will be assessed by measurements of the fatty acid profile in serum, sampled at inclusion, after 12 months and at the end of study.
Discussion
The OMEMI study is scheduled to terminate when the last included patient has been followed for 2 years. To the best of our knowledge, the OMEMI study is the first to evaluate the effect of n-3 PUFAs on CVDs and mortality in a high risk elderly population having suffered an acute myocardial infarction.
Trial registration
ClinicalTrials.gov, NCT01841944
doi:10.1186/1471-2318-14-74
PMCID: PMC4074832  PMID: 24928284
Omega 3 fatty acids; Acute myocardial infarction; Randomized placebo controlled trial; Elderly
2.  The Time Profile of Pentraxin 3 in Patients with Acute ST-Elevation Myocardial Infarction and Stable Angina Pectoris Undergoing Percutaneous Coronary Intervention 
Mediators of Inflammation  2014;2014:608414.
Background. High levels of Pentraxin 3 (PTX3) are reported in acute myocardial infarction (AMI). Aim. To investigate circulating levels and gene expression of PTX3 in patients with AMI and stable angina pectoris (AP) undergoing PCI. Methods. Ten patients with AP and 20 patients with AMI were included. Blood samples were drawn before PCI in the AP group and after 3 and 12 hours and days 1, 3, 5, 7, and 14 in both groups. Results. Circulating PTX3 levels were higher in AMI compared to AP at 3 and 12 hours (P < 0.001 and P = 0.003). Within the AMI group, reduction from 3 hours to all later time points was observed (all P ≤ 0.001). Within the AP group, increase from baseline to 3 hours (P = 0.022), followed by reductions thereafter (all P < 0.05), was observed. PTX3 mRNA increased in the AMI group from 3 hours to days 7 and 14 in a relative manner of 62% and 73%, while a relative reduction from baseline to 3 and 12 hours of 29% and 37% was seen in the AP group. Conclusion. High circulating PTX3 levels shortly after PCI in AMI indicate that AMI itself influences PTX3 levels. PTX3 mRNA might be in response to fluctuations in circulating levels.
doi:10.1155/2014/608414
PMCID: PMC3967811  PMID: 24737925
3.  Insulin levels and HOMA index are associated with exercise capacity in patients with type 2 diabetes and coronary artery disease 
Background
Previous studies on type 2 diabetes have shown an association between exercise capacity and insulin resistance. In patients with coronary artery disease (CAD) exercise capacity is often reduced due to exercise-induced ischemia. We have investigated the association between glucometabolic control, including the homeostatic model assessment (HOMA) of insulin resistance, and exercise capacity in patients with type 2 diabetes and CAD with and without exercise-induced ischemia.
Methods
In 137 patients (age 63.1 ± 7.9) cardiopulmonary exercise testing on treadmill was performed using a modified Balke protocol. The highest oxygen uptake (VO2peak) was reported as 30-s average. Fasting blood samples were drawn for determination of glucose, insulin and HbA1c. Insulin resistance (IR) was assessed by the HOMA2-IR computer model. Exercise-induced ischemia was defined as angina and/ or ST-depression in ECG ≥ 0.1 mV during the exercise test.
Results
HOMA2-IR was inversely correlated to VO2peak (r = -0.328, p < 0.001), still significant after adjusting for age, gender, smoking and BMI. Patients with HOMA2-IR above the median value (1.3) had an adjusted odds ratio of 3.26 (95 % CI 1.35 to 7.83, p = 0.008) for having VO2peak below median (23.8 mL/kg/min). Insulin levels were inversely correlated to VO2peak (r = -0.245, p = 0.010), also after adjusting for age and gender, but not after additional adjustment for BMI. The correlation between HOMA2-IR and VO2peak was also significant in the subgroups with (n = 51) and without exercise-induced ischemia (n = 86), being numerically stronger in the group with ischemia (r = -0.430, p = 0.003 and r = -0.276, p = 0.014, respectively). Fasting glucose and HbA1c were not correlated with VO2peak or AT.
Conclusions
Insulin resistance, as estimated by fasting insulin and the HOMA index, was inversely associated with exercise capacity in patients with type 2 diabetes and CAD, the association being more pronounced in the subgroup with exercise-induced ischemia. These results indicate that insulin resistance is related to exercise capacity in type 2 diabetic patients with CAD, possibly even more so in patients with exercise-induced ischemia compared to those without.
doi:10.1186/1758-5996-6-36
PMCID: PMC3984726  PMID: 24612649
Coronary artery disease; Type 2 diabetes; Insulin resistance; HOMA index; VO2max
4.  IL-6 signalling in patients with acute ST-elevation myocardial infarction 
Results in Immunology  2013;4:8-13.
Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI.
In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state.
In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated.
Highlights
•Circulating levels of IL-6 and CRP, but not sgp130 and sIL-6R were associated with the extent of myocardial necrosis.•Circulating levels of sgp130 were weakly associated with impaired LV function and glucometabolic state.•Circulating levels of sIL-6R were not associated with either impaired LV function or glucometabolic state.
doi:10.1016/j.rinim.2013.11.002
PMCID: PMC4009406
ST-elevation myocardial infarction; IL-6; sgp130; sIL-6R; Myocardial necrosis; sgp130, soluble glycoprotein 130; sIL-6R, soluble interleukin -6 receptor; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; LVEF, left ventricular ejection fraction
5.  IL-6 signalling in patients with acute ST-elevation myocardial infarction 
Results in Immunology  2013;4:8-13.
Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI.
In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state.
In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated.
Highlights
•Circulating levels of IL-6 and CRP, but not sgp130 and sIL-6R were associated with the extent of myocardial necrosis.•Circulating levels of sgp130 were weakly associated with impaired LV function and glucometabolic state.•Circulating levels of sIL-6R were not associated with either impaired LV function or glucometabolic state.
doi:10.1016/j.rinim.2013.11.002
PMCID: PMC3973821  PMID: 24707455
ST-elevation myocardial infarction; IL-6; sgp130; sIL-6R; Myocardial necrosis; sgp130, soluble glycoprotein 130; sIL-6R, soluble interleukin -6 receptor; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; LVEF, left ventricular ejection fraction
6.  The Co-Existence of the IL-18+183 A/G and MMP-9 -1562 C/T Polymorphisms Is Associated with Clinical Events in Coronary Artery Disease Patients 
PLoS ONE  2013;8(9):e74498.
Objective
Interleukin (IL)-18 has been associated with severity of atherosclerosis and discussed to predict cardiovascular (CV) events. We have previously shown that the IL-18+183 G-allele significantly reduces IL-18 levels. This study was aimed to investigate the prognostic significance of the IL-18+183 A/G polymorphism (rs5744292), single and in coexistence with the matrix metalloproteinase (MMP)-9 -1562 C/T (rs3918242) polymorphism, in patients with stable coronary artery disease (CAD). Serum levels of IL-18, MMP-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were additionally assessed.
Methods
1001 patients with angiographically verified CAD were genotyped and the biomarkers were measured accordingly. After two years follow-up, 10.6% experienced new clinical events; acute myocardial infarction (AMI), stroke, unstable angina pectoris and death.
Results
The IL-18+183 G-allele associated with 35% risk reduction in composite endpoints after adjusting for potential covariates (p = 0.044). The IL-18+183 AA/MMP-9 -1562 CT/TT combined genotypes associated with a significant increase in risk of composite endpoints (OR = 1.87; 95% CI = 1.13–3.11, p = 0.015, adjusted). Patients with clinical events presented with significantly higher IL-18 levels as compared to patients without (p = 0.011, adjusted). The upper tertile of IL-18 levels associated with an increase in risk of AMI as compared to lower tertiles (OR = 2.36; 95% CI = 1.20–4.64, p = 0.013, adjusted).
Conclusion
The IL-18+183 A/G polymorphism, single and in combination with MMP-9 genotypes, may influence the risk of clinical events in stable CAD patients.
doi:10.1371/journal.pone.0074498
PMCID: PMC3764212  PMID: 24040261
7.  Prothrombotic markers in patients with acute myocardial infarction and left ventricular thrombus formation treated with pci and dual antiplatelet therapy 
Thrombosis Journal  2013;11:1.
Background
The aim of the present study was to compare circulating levels of selected prothrombotic markers in patients suffering acute myocardial infarction (AMI) with and without left ventricular (LV) thrombus.
Methods
One hundred patients with AMI treated with PCI on the LAD and dual antiplatelet therapy were included. LV thrombus formation was detected by echocardiography and/or MRI in 15 patients. Fasting blood samples were drawn 4–5 days (baseline), 6–7 days, 8–9 days, 2–3 weeks and 3 months after the AMI for determination of haemostatic markers.
Results
We found higher levels of soluble tissue factor (TF) and D-dimer in the LV thrombus group 4–5 days, 8–9 days and 3 months (only TF) after the AMI compared to the patients without thrombus formation (p<0.05). Patients with TF in the upper quartile at baseline had significantly higher risk for LV thrombus (OR 4.2; 95% CI 1.2 -14.5; p=0.02, adjusted for infarct size).
The levels of prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were significantly lower in the thrombus group after 8–9 days (only ETP), 2–3 weeks and 3 months. The levels of plasminogen activator inhibitor 1 activity and tissue plasminogen activator antigen did not differ between the groups.
Conclusion
In the acute phase of AMI, we found higher levels of TF and D-dimer in the LV thrombus group, indicating hypercoagulability of possible importance for the generation of mural thrombus. Lower levels of F1+2, ETP and D-dimer in the thrombus group late during follow-up are probably induced by the initiated anticoagulation therapy.
doi:10.1186/1477-9560-11-1
PMCID: PMC3554510  PMID: 23311309
Acute myocardial infarction; Haemostatic markers; Inflammation; Left ventricular thrombus formation
8.  Markers of hypercoagulability in CAD patients. Effects of single aspirin and clopidogrel treatment 
Thrombosis Journal  2012;10:12.
Background
Cardiovascular disease with disturbances in the haemostatic system, might lead to thrombotic complications with clinical manifestations like acute myocardial infarction (AMI) and stroke. Activation of the coagulation cascade with subsequent increased thrombin generation, characterizes a prothrombotic phenotype. In the present study we investigated whether prothrombotic markers were associated with risk factors and clinical subgroups in a cohort of patients with angiographically verified coronary artery disease (CAD). The patients were randomized to long-term treatment with the antiplatelet drugs aspirin or clopidogrel, and we further investigated the effect on hypercoagulability of such treatment for 1 year, of which limited data exists.
Methods
Venous blood samples were collected in fasting condition between 08:00 and 10:30 am, at baseline when all patients were on aspirin therapy (n = 1001) and in 276 patients after 1 year follow-up on aspirin or clopidogrel. In vivo thrombin generation was assessed by prothrombin fragment 1 + 2 (F1+2) and D-dimer, and the endogenous thrombin potentiale (ETP) in the calibrated automated thrombogram (CAT) assay, representing ex vivo thrombin generation. In addition soluble tissue factor (sTF) and free- and total tissue factor pathway inhibitor (TFPI) were measured.
Results
We found age to be significantly associated with F1+2 and D-dimer (β = 0.229 and β =0.417 respectively, p <0.001, both). Otherwise, only weak associations were found. F1+2 and D-dimer were higher in women compared to men (p <0.001 and p = 0.033, respectively). Smokers had elevated levels of ETP compared to non-smokers (p = 0.014). Additionally, patients on renin-angiotensin system (RAS) inhibition showed significantly higher levels of F1+2, compared to non-users (p = 0.013). Both aspirin and clopidogrel reduced levels of ETP after 12 months intervention (p = 0.003 and p <0.001, respectively) and the levels of F1+2 were significantly more reduced on aspirin compared to clopidogrel (p = 0.023).
Conclusions
In the present population of stable CAD, we could demonstrate a more hypercoagulable profile among women, smokers and patients on RAS medication, assessed by the prothrombotic markers F1+2, D-dimer and ETP. Long-term antiplatelet treatment with aspirin alone seems to attenuate thrombin generation to a greater extent than with clopidogrel alone. The study is registered at http://www.clinicaltrials.gov: NCT00222261.
doi:10.1186/1477-9560-10-12
PMCID: PMC3552672  PMID: 22883224
Thrombin generation; Coronary artery disease; Hypercoagulability; Prothrombotic markers; The CAT assay; Endogenous thrombin potentiale; Antiplatelet treatment; Aspirin; Clopidogrel
9.  High On-Aspirin Platelet Reactivity and Clinical Outcome in Patients With Stable Coronary Artery Disease: Results From ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial) 
Background
Patients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor.
Methods and Results
In this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16).
Conclusions
In stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.)
doi:10.1161/JAHA.112.000703
PMCID: PMC3487336  PMID: 23130135
antiplatelet therapy; aspirin; clopidogrel; residual platelet reactivity; angina, stable
10.  Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an Observational Study 
Background
Increased IL-18 serum levels have been associated with diabetes type 2, metabolic syndrome and the severity of atherosclerosis. The present study investigated the presence and influence of IL-18 genetic variants on gene- and protein expression in stable coronary artery disease (CAD) patients.
Methods
The +183 A/G (rs 5744292), -137 G/C (rs 187238) and -607 C/A (rs 1946518) polymorphisms were determined in 1001 patients with angiographically verified stable CAD, and in 204 healthy controls. IL-18 gene-expression was measured in circulating leukocytes in 240 randomly selected patients. Circulating IL-18 and IL-18 binding protein levels were measured immunologically in all patients.
Results
The +183 G-allele associated significantly with lower serum levels of IL-18 (p = 0.002, adjusted for age, glucose, body mass index and gender) and a 1.13- fold higher IL-18 gene-expression (p = 0.010). No influence was observed for the -137 G/C and -607 C/A polymorphisms. The IL-18 binding protein levels were not influenced by IL-18 genotypes. IL-18 levels were significantly higher in men as compared to women, and in patients with diabetes type 2 and metabolic syndrome compared to those without (p ≤ 0.001, all). The reduction in IL-18 levels according to the +183 G-allele was 3-4 fold more pronounced in diabetes and metabolic syndrome as compared to unaffected patients.
Finally, the +183 AA genotype was more frequent in patients with hypertension (p = 0.042, adjusted for age, body mass index and gender).
Conclusion
The reduction in serum IL-18 levels across increasing numbers of +183G-alleles was especially apparent in patient with diabetes type 2 and metabolic syndrome, suggesting a beneficial GG genotype in relation to cardiovascular outcome in these patients.
Clinical Trial Registration Number
ClinicalTrials.gov: NCT00222261
doi:10.1186/1475-2840-10-110
PMCID: PMC3295692  PMID: 22141572
Single nucleotide polymorphisms; IL-18 mRNA; diabetes type 2; metabolic syndrome; hypertension
11.  Impact of newly diagnosed abnormal glucose regulation on long-term prognosis in low risk patients with ST-elevation myocardial infarction: A follow-up study 
Background
Patients with acute myocardial infarction and newly detected abnormal glucose regulation have been shown to have a less favourable prognosis compared to patients with normal glucose regulation. The importance and timing of oral glucose tolerance testing (OGTT) in patients with acute myocardial infarction without known diabetes is uncertain. The aim of the present study was to evaluate the impact of abnormal glucose regulation classified by an OGTT in-hospital and at three-month follow-up on clinical outcome in patients with acute ST elevation myocardial infarction (STEMI) without known diabetes.
Methods
Patients (n = 224, age 58 years) with a primary percutanous coronary intervention (PCI) treated STEMI were followed for clinical events (all-cause mortality, non-fatal myocardial re-infarction, recurrent ischemia causing hospital admission, and stroke). The patients were classified by a standardised 75 g OGTT at two time points, first, at a median time of 16.5 hours after hospital admission, then at three-month follow-up. Based on the OGTT results, the patients were categorised according to the WHO criteria and the term abnormal glucose regulation was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.
Results
The number of patients diagnosed with abnormal glucose regulation in-hospital and at three-month was 105 (47%) and 50 (25%), respectively. During the follow up time of (median) 33 (27, 39) months, 58 (25.9%) patients experienced a new clinical event. There were six deaths, 15 non-fatal re-infarction, 33 recurrent ischemia, and four strokes. Kaplan-Meier analysis of survival free of composite end-points showed similar results in patients with abnormal and normal glucose regulation, both when classified in-hospital (p = 0.4) and re-classified three months later (p = 0.3).
Conclusions
Patients with a primary PCI treated STEMI, without previously known diabetes, appear to have an excellent long-term prognosis, independent of the glucometabolic state classified by an OGTT in-hospital or at three-month follow-up.
Trial registration
The trial is registered at http://www.clinicaltrials.gov, NCT00926133.
doi:10.1186/1472-6823-11-14
PMCID: PMC3173358  PMID: 21801387
12.  The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel 
Thrombosis Journal  2011;9:4.
Background
Different platelet function tests can be used to evaluate the degree of achieved platelet inhibition in patients treated with clopidogrel. The presence of CYP 2C19*2 polymorphism can reduce the formation of the active metabolite of clopidogrel, resulting in less platelet inhibition.
Patients and Methods
Patients with symptomatic coronary artery disease, all on chronic single aspirin treatment were randomized to continue on aspirin or change to clopidogrel. In 219 randomly selected clopidogrel treated patients, platelet reactivity was evaluated by VASP-PRI determination and by use of VerifyNow P2Y12-PRU. The CYP 2C19*2 G/A polymorphism was further determined.
Results
The total frequency of clopidogrel resistance was 29.0% by VASP-PRI and 31.6% by VerifyNow-PRU. The number of patients being hetero- and homozygous combined for the CYP 2C19*2 polymorphism (GA/AA) was 64 (29%). Platelet reactivity was significantly higher in patients with the polymorphism compared to wild-type patients (GG). VASP-PRI was 50.9% (SD19) in patients having the polymorphism compared to 38.3% (SD21) in patients with the GG genotype (p = 0.001). Correspondingly, the mean PRU was 165 (SD67) compared to 124 (SD69) (p < 0.001). The frequency of clopidogrel resistance in patients with the polymorphism was 32% compared to 16% in wild-type patients when defined by VASP-PRI (p = 0.006). When defined by PRU (VerifyNow), the corresponding frequencies were 53% and 22% (p < 0.001).
Conclusions
Clopidogrel treated patients with the CYP 2C19*2 polymorphism have significantly increased platelet reactivity compared to patients with the wild-type, evaluated with the VASP determination, and even more pronounced with the VerifyNow P2Y12 method.
Trial Registration
ClinicalTrials.gov: NCT00222261
doi:10.1186/1477-9560-9-4
PMCID: PMC3071307  PMID: 21426546
Clopidogrel resistance; Functional tests; VerifyNow method; VASP method; Genetic polymorphisms
13.  Regional myocardial function after intracoronary bone marrow cell injection in reperfused anterior wall infarction - a cardiovascular magnetic resonance tagging study 
Background
Trials have brought diverse results of bone marrow stem cell treatment in necrotic myocardium. This substudy from the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial (ASTAMI) explored global and regional myocardial function after intracoronary injection of autologous mononuclear bone marrow cells (mBMC) in acute anterior wall myocardial infarction treated with percutaneous coronary intervention.
Methods
Cardiovascular magnetic resonance (CMR) tagging was performed 2-3 weeks and 6 months after revascularization in 15 patients treated with intracoronary stem cell injection (mBMC group) and in 13 controls without sham injection. Global and regional left ventricular (LV) strain and LV twist were correlated to cine CMR and late gadolinium enhancement (LGE).
Results
In the control group myocardial function as measured by strain improved for the global LV (6 months: -13.1 ± 2.4 versus 2-3 weeks: -11.9 ± 3.4%, p = 0.014) and for the infarct zone (-11.8 ± 3.0 versus -9.3 ± 4.1%, p = 0.001), and significantly more than in the mBMC group (inter-group p = 0.027 for global strain, respectively p = 0.009 for infarct zone strain). LV infarct mass decreased (35.7 ± 20.4 versus 45.7 ± 29.5 g, p = 0.024), also significantly more pronounced than the mBMC group (inter-group p = 0.034). LV twist was initially low and remained unchanged irrespective of therapy.
Conclusions
LGE and strain findings quite similarly demonstrate subtle differences between the mBMC and control groups. Intracoronary injection of autologous mBMC did not strengthen regional or global myocardial function in this substudy.
Trial registration
ClinicalTrials.gov: NCT00199823
doi:10.1186/1532-429X-13-22
PMCID: PMC3068099  PMID: 21414223
14.  Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers 
BMC Medicine  2010;8:54.
Background
Plant-based diets rich in fruit and vegetables can prevent development of several chronic age-related diseases. However, the mechanisms behind this protective effect are not elucidated. We have tested the hypothesis that intake of antioxidant-rich foods can affect groups of genes associated with cellular stress defence in human blood cells. Trial registration number: NCT00520819 http://clinicaltrials.gov.
Methods
In an 8-week dietary intervention study, 102 healthy male smokers were randomised to either a diet rich in various antioxidant-rich foods, a kiwifruit diet (three kiwifruits/d added to the regular diet) or a control group. Blood cell gene expression profiles were obtained from 10 randomly selected individuals of each group. Diet-induced changes on gene expression were compared to controls using a novel application of the gene set enrichment analysis (GSEA) on transcription profiles obtained using Affymetrix HG-U133-Plus 2.0 whole genome arrays.
Results
Changes were observed in the blood cell gene expression profiles in both intervention groups when compared to the control group. Groups of genes involved in regulation of cellular stress defence, such as DNA repair, apoptosis and hypoxia, were significantly upregulated (GSEA, FDR q-values < 5%) by both diets compared to the control group. Genes with common regulatory motifs for aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (AhR/ARNT) were upregulated by both interventions (FDR q-values < 5%). Plasma antioxidant biomarkers (polyphenols/carotenoids) increased in both groups.
Conclusions
The observed changes in the blood cell gene expression profiles suggest that the beneficial effects of a plant-based diet on human health may be mediated through optimization of defence processes.
doi:10.1186/1741-7015-8-54
PMCID: PMC2955589  PMID: 20846424
15.  Increased levels of CRP and MCP-1 are associated with previously unknown abnormal glucose regulation in patients with acute STEMI: a cohort study 
Background
Inflammation plays an important role in the pathophysiology of both atherosclerosis and type 2 diabetes and some inflammatory markers may also predict the risk of developing type 2 diabetes. The aims of the present study were to assess a potential association between circulating levels of inflammatory markers and hyperglycaemia measured during an acute ST-elevation myocardial infarction (STEMI) in patients without known diabetes, and to determine whether circulating levels of inflammatory markers measured early after an acute STEMI, were associated with the presence of abnormal glucose regulation classified by an oral glucose tolerance test (OGTT) at three-month follow-up in the same cohort.
Methods
Inflammatory markers were measured in fasting blood samples from 201 stable patients at a median time of 16.5 hours after a primary percutanous coronary intervention (PCI). Three months later the patients performed a standardised OGTT. The term abnormal glucose regulation was defined as the sum of the three pathological glucose categories classified according to the WHO criteria (patients with abnormal glucose regulation, n = 50).
Results
No association was found between inflammatory markers and hyperglycaemia measured during the acute STEMI. However, the levels of C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) measured in-hospital were higher in patients classified three months later as having abnormal compared to normal glucose regulation (p = 0.031 and p = 0.016, respectively). High levels of CRP (≥ 75 percentiles (33.13 mg/L)) and MCP-1 (≥ 25 percentiles (190 ug/mL)) were associated with abnormal glucose regulation with an adjusted OR of 3.2 (95% CI 1.5, 6.8) and 7.6 (95% CI 1.7, 34.2), respectively.
Conclusion
Elevated levels of CRP and MCP-1 measured in patients early after an acute STEMI were associated with abnormal glucose regulation classified by an OGTT at three-month follow-up. No significant associations were observed between inflammatory markers and hyperglycaemia measured during the acute STEMI.
doi:10.1186/1475-2840-9-47
PMCID: PMC2940874  PMID: 20809989
16.  Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes 
Thrombosis Journal  2010;8:7.
Background
Tissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population.
Methods
Patients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5'upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5'upstream region and the TFPI -33T/C in intron 7.
Results
No significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type-2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both).
The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both).
Conclusion
Genetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.
doi:10.1186/1477-9560-8-7
PMCID: PMC2882354  PMID: 20444258
17.  The role of interleukin-18 in the metabolic syndrome 
The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions.
doi:10.1186/1475-2840-9-11
PMCID: PMC2858122  PMID: 20331890
18.  Interleukin-18 Is a Strong Predictor of Cardiovascular Events in Elderly Men With the Metabolic Syndrome 
Diabetes Care  2009;32(3):486-492.
OBJECTIVE—The aim of this study was to investigate the role of inflammatory markers as potential predictors of cardiovascular events in subjects with and without the metabolic syndrome.
RESEARCH DESIGN AND METHODS—This was a post hoc analysis from the Diet and Omega-3 Intervention Trial (DOIT), comprising 563 elderly men with (n = 221) and without (n = 342) metabolic syndrome. Circulating inflammatory markers were measured.
RESULTS—During 3 years, 68 cardiovascular events were recorded. In the total population, C-reactive protein (CRP) (P < 0.001), interleukin-18 (IL-18) (P = 0.008), and IL-6 (P = 0.003) were elevated in subjects with events. In subjects with metabolic syndrome, IL-18 was the strongest predictor (adjusted odds ratio 2.9 [95% CI 1.1–7.8]). In subjects without metabolic syndrome, only CRP seemed to be an independent predictor (3.3 [1.5–7.3]). There was a significant interaction between fasting glucose and IL-18 (P = 0.008) and IL-6 (P = 0.024) but not CRP. Elevated fasting glucose (>6.2 mmol/l) markedly increased the predictive power of inflammatory markers (IL-18: 5.5 [1.4–21.1], IL-6: 3.5 [1.0–11.8], and CRP: 3.5 [1.0–11.9]). For IL-18, there was a stepwise increase in event rate by quartiles of fasting glucose.
CONCLUSIONS—IL-18 was an independent predictor of cardiovascular events in subjects with metabolic syndrome and even more so in the presence of elevated fasting glucose. Our findings suggest a mutually potentiating effect of hyperglycemia and inflammation in cardiovascular risk prediction.
doi:10.2337/dc08-1710
PMCID: PMC2646034  PMID: 19092166
19.  Abnormal glucose regulation in patients with acute ST- elevation myocardial infarction-a cohort study on 224 patients 
Background
A high prevalence of impaired glucose tolerance and unknown type 2-diabetes in patients with coronary heart disease and no previous diagnosis of diabetes have been reported. The aims of the present study were to investigate the prevalence of abnormal glucose regulation (AGR) 3 months after an acute ST-elevation myocardial infarction (STEMI) in patients without known glucometabolic disturbance, to evaluate the reliability of a 75-g oral glucose tolerance test (OGTT) performed very early after an acute STEMI to predict the presence of AGR at 3 months, and to study other potential predictors measured in-hospital for AGR at 3 months.
Methods
This was an observational cohort study prospectively enrolling 224 STEMI patients treated with primary PCI. An OGTT was performed very early after an acute STEMI and was repeated in 200 patients after 3 months. We summarised the exact agreement observed, and assessed the observed reproducibility of the OGTTs performed in-hospital and at follow up. The patients were classified into glucometabolic categories defined according to the World Health Organisation criteria. AGR was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.
Results
The prevalence of AGR at three months was 24.9% (95% CI 19.1, 31.4%), reduced from 46.9% (95% CI 40.2, 53.6) when measured in-hospital. Only, 108 of 201 (54%) patients remained in the same glucometabolic category after a repeated OGTT. High levels of HbA1c and admission plasma glucose in-hospital significantly predicted AGR at 3 months (p < 0.001, p = 0.040, respectively), and fasting plasma glucose was predictive when patients with large myocardial infarction were excluded (p < 0.001).
Conclusion
The prevalence of AGR in STEMI patients was lower than expected. HbA1c, admission plasma glucose and fasting plasma glucose measured in-hospital seem to be useful as early markers of longstanding glucometabolic disturbance. An OGTT performed very early after a STEMI did not provide reliable information on long-term glucometabolic state and should probably not be recommended.
doi:10.1186/1475-2840-8-6
PMCID: PMC2646717  PMID: 19183453
20.  Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction 
Thrombosis Journal  2008;6:7.
Background
Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.
Aims
The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).
Methods
Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.
Results
The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.
Conclusion
CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.
doi:10.1186/1477-9560-6-7
PMCID: PMC2440373  PMID: 18559094
21.  Effect of diet and omega-3 fatty acid intervention on asymmetric dimethylarginine 
Background and aim
Impaired vasodilatation has been suggested to be caused by inhibition of nitric oxide generation by the recently described asymmetric dimethylarginine (ADMA). In the present study we wanted to explore whether n-3 polyunsaturated fatty acid (PUFA) supplementation and/or diet intervention have beneficial influence on endothelial function assessed as plasma levels of ADMA and L-arginine.
Methods
A male population (n = 563, age 70 ± 6 yrs) with long-standing hyperlipidemia, characterized as high risk individuals in 1970–72, was included, randomly allocated to receive placebo n-3 PUFA capsules (corn oil) and no dietary advice (control group), dietary advice (Mediterranean type), n-3 PUFA capsules, or dietary advice and n-3 PUFA combined and followed for 3 years. Fasting blood samples were drawn at baseline and the end of the study.
Results
Compliance with both intervention regimens were demonstrated by changes in serum fatty acids and by recordings from a food frequency questionnaire. No influence of either regimens on ADMA levels were obtained. However, n-3 PUFA supplementation was accompanied by a significant increase in L-arginine levels, different from the decrease observed in the placebo group (p < 0.05). In individuals with low body mass index (<26 kg/m2), the decrease in L-arginine on placebo was strengthened (p = 0.01), and the L-arginine/ADMA ratio was also significantly reduced (p = 0.04).
Conclusion
In this rather large randomized intervention study, ADMA levels were not influenced by n-3 PUFA supplementation or dietary counselling. n-3 PUFA did, however, counteract the age-related reduction in L-arginine seen on placebo, especially in lean individuals, which might be discussed as an improvement of endothelial function.
doi:10.1186/1743-7075-3-4
PMCID: PMC1343562  PMID: 16396682

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