Myocardial Infarction
Conditions
Keywords
acute myocardial infarction, diet therapy, anthocyanin, bilberry bush, exercise capacity, cholesterol, beta glucans, type 2 diabetes mellitus
Brief summary
Background: Bilberries from Sweden, rich in polyphenols, have shown cholesterol-lowering effects in small studies, and the cholesterol-lowering properties of oats, with abundant beta-glucans and potentially bioactive phytochemicals, are well established. Both may provide cardiometabolic benefits for patients with manifest chronic cardiometabolic disease, such as type 2 diabets mellitus (T2DM) and myocardial infarction (MI). However, large studies of adequate statistical power and appropriate duration are needed to confirm clinically relevant treatment effects. No previous study has evaluated the potential additive or synergistic effects of bilberry combined with oats on cardiometabolic risk factors. Design: This is a double-blind, randomized, placebo-controlled clinical trial. Our primary objective is to assess cardioprotective effects of diet supplementation with dried bilberry and with bioprocessed oat bran, with a secondary explorative objective of assessing their combination, compared with a neutral isocaloric reference supplement, for patients diagnosed with T2DM and/or MI. Patients will be randomized 1:1:1:1 to a three-month intervention. The primary endpoint is the difference in LDL cholesterol change between the intervention groups after three months. The major secondary endpoint is exercise capacity at three months. Other secondary endpoints include plasma concentrations of biochemical markers of inflammation, glycaemia, and gut microbiota composition after three months. Implications: Secondary prevention after cardiometabolic disease, including T2DM and MI, has improved during the last decades but diabetes complications, readmissions and cadiovascular related deaths following these conditions remain large health care challenges. Controlling hyperlipidemia, hyperglycaemia, hypertension and inflammation is critical to preventing (new) cardiovascular events, but novel pharmacological treatments for these conditions are expensive and associated with negative side effects. If bilberry and/or oat, in addition to standard medical therapy, can lower LDL cholesterol and inflammation more than standard therapy alone, this could be a cost-effective and safe dietary strategy for secondary prevention in high-risk patients or risk prevention in subjects with T2DM.
Interventions
DIETARY_SUPPLEMENTBilberry
The dietary intervention will continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture as both oat and bilberry), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period.
DIETARY_SUPPLEMENTPlacebo
The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period.
DIETARY_SUPPLEMENTBioprocessed oat bran
The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period.
DIETARY_SUPPLEMENTCombination bilberry/oats
The dietary intervention will be continued for three months. After randomization, participants will be given bilberry shakes (active), liquid oat shakes (active), a combination shake with bilberry and oats, or reference shakes (placebo product containing no active bilberry or active oats but with similar taste and texture), for intake two times a day (t.i.d). The formula for the shakes to be used in the intervention will be finalized during the initial project period.
Sponsors
Ole Frobert, MD, PhD
Region Västmanland
Region Skane
Chalmers University of Technology
Värmland County Council, Sweden
Vastra Gotaland Region
Aarhus University Hospital
Odense University Hospital
Falu Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed T2DM diagnosis (any treatment modality accepted) and/or within 3 years post STEMI or NSTEMI * Completed coronary angiography/PCI * Male and female subjects ≥18 years * Allocated to atorvastatin at a daily dose of 80 mg (only eligible for patients enrolled up to 7 days post MI and not for T2D subjects) * Written informed consent
Exclusion criteria
* Emergency coronary artery bypass grafting * \<18 years of age * LDL cholesterol \<2.0 mmol/L * Daily intake or the intent to initiate daily intake of bilberry in any form or daily intake of \>15 g of oatmeal or equivalent * Food allergy/intolerance to gluten, bilberries or legumes * Previous randomization in the BioDiaMI trial * Inability to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma levels of LDL cholesterol | Three months | The effect of intervention on difference between the groups of LDL cholesterol after three months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma lipid profile | Three months | The effect of intervention on differences between the groups of fasting lipid profile including HDL, triglycerides, total cholesterol, small-dense LDL cholesterol, apo A, apo B, Lp(a) and oxidized LDL. |
| Symptom-limited bicycle ergometer test | Three months | The effect of intervention on exercise capacity (measured as maximal workload in Watts and as estimated maximal oxygen uptake (VO2 max)) |
| Dynamic unilateral heel-lft and unilateral shoulder flexion tests | Three months | The effect of intervention on muscle endurance |
| Self-reported physical activity level | Three months | The effect of intervention on the Frändin/Grimby activity scale (6 levels of physical activity, min:1 (low activity) max:6 (heavy activity)) and the Haskell physical activity scale ("For how many days were you physically active during the last week for at least 20 minutes?", min:0 max:7) |
| Plasma Cardiac Troponin Concentration | Three months | Change in plasma cardiac troponin (high-sensitivity cardiac troponin T or I) concentration from baseline to 3 months to assess myocardial injury. The effect of intervention on Troponin levels, Unit of Measure: ng/L |
| Plasma NT-proBNP Concentration | Three months | Change in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline to 3 months to assess cardiac stress, pg/mL |
| Plasma hs-CRP Concentration | Three months | Change in plasma high-sensitivity C-reactive protein (hs-CRP) concentration from baseline to 3 months to assess systemic inflammation. Unit of Measure: mg/L |
| Plasma IL-6 Concentration | Three months | Change in plasma interleukin-6 (IL-6) concentration from baseline to 3 months to assess inflammatory response. Unit of Measure: pg/mL |
| Glycosylated Hemoglobin (HbA1c) | Three months | Change in glycosylated hemoglobin (HbA1c) from baseline to 3 months to assess glycemic control. Unit of Measure: % |
| Fasting Plasma Insulin Concentration | Three months | Change in fasting plasma insulin concentration from baseline to 3 months to assess insulin sensitivity and metabolic status. Unit of Measure: µIU/mL (micro-international units per milliliter) |
| Fasting Plasma C-Peptide Concentration | Three months | Change in fasting plasma C-peptide concentration from baseline to 3 months to assess endogenous insulin secretion and beta-cell function. Unit of Measure: ng/mL |
| Serum Creatinine Concentration | Three months | Change in serum creatinine concentration from baseline to 3 months to assess renal function. Unit of Measure: mg/dL |
| Fasting Plasma Glucose Concentration | Three months | Change in fasting plasma glucose concentration from baseline to 3 months to assess glycemic control. Unit of Measure: mg/dL Unit of Measure: mg/dL |
| Serum Cystatin C Concentration | Three months | Change in serum cystatin C concentration from baseline to 3 months to assess renal function and estimate glomerular filtration independent of muscle mass. Unit of Measure: mg/L Unit of Measure: mg/dL Unit of Measure: mg/dL |
| Untargeted plasma metabolome | Three months | Untargeted plasma metabolomics will be employed to exploratively assess alterations in endogenous and exposome-related metabolites and to identify metabolites that may differ with treatment. |
| Fecal samples of gut microbiota composition | Three months | These exploratory analyses of will allow to investigate the extent to which gut microbiota composition and activity differs between responders and non-responders to the interventions. |
| Left ventricular systolic function | Three months | The effect of intervention on left ventricular function. Baseline left ventricular systolic function, expressed as global ejection fraction in percent according to the biplane Simpson method, will be evaluated by echocardiography by the discharging physician. The procedure will be repeated after three months by an experienced echocardiography technician blinded to results of the initial examinations |
| Resting heart rate | Three months | The effect of intervention on resting heart rate |
| Systolic and diastolic blood pressure | Three months | The effect of intervention on blood pressure (mmHg) |
| Urine albumin-creatinine ratio | Three months | Urine albumin-creatinine ratio will be measured for for T2DM only |
| Continuous glucose monitoring with Continuous Glucose Monitors (CGM) - FreeStyle model 2 | Three months | Continuous glucose monitoring (in a subset of T2DM only, n=100 in total) |
| Body composition with multi-frequency bioimpedance | Three months | The effect of intervention on body composition measured with multi-frequency bioimpedance (for T2DM only) |
| Diabetic retinal changes | Three months | The effect of intervention on diabetic retinal changes (eye fundus examination) (in a subset of T2DM only, n=100 in total) |
| Platelet aggregation (Primary hemostasis) | Three months | Ex vivo platelet aggregation in whole blood measured with impedance aggregometry (Multiplate®, Roche, Switzerland) after stimulation with adenosine diphosphate (ADP), arachidonic acid and thrombin-related activation peptide (TRAP-6). Unit of measure: Aggregation units x min. (in a subset of T2DM only, n=100 in total) |
| P-selectin levels (Primary hemostasis) | Three months | Plasma concentration of P-selectin measured with commercial ELISA (CD62P Quantikine, Biotechne, Dublin, Ireland). Unit of measure: ng/mL. (in a subset of T2DM only, n=100 in total) |
| Ex vivo thrombin generation (Secondary hemostasis) | Three months | Ex vivo thrombin generation (endogenous thrombin potential) in platelet-poor plasma measured using Calibrated Automated Thrombogram (BV Thrombinoscope, Maastricht, the Netherlands) after stimulation with tissue factor. Unit of measure: nM x min. (in a subset of T2DM only, n=100 in total) |
| Prothrombin fragment 1+2 (Secondary hemostasis) | Three months | Plasma concentration of prothrombin fragment 1+2, measured with commercial ELISA (EnzygnostTM, Siemens Healthineers, Ballerup, Denmark). Unit of measure: pmol/L. (in a subset of T2DM only, n=100 in total) |
| Fibrinolysis speed | Three months | Ex vivo fibrinolytic capacity (fibrinolysis speed) in whole blood measured with in-house modified rotational thromboelastometry after stimulation with tissue factor and tissue plasminogen activator. Unit of measure: mm/min. (in a subset of T2DM only, n=100 in total) |
| Fibrinolytic capacity | Three months | Ex vivo fibrinolytic capacity (time from peak fibrin to 50% lysis) in platelet-poor plasma measured with in-house turbidimetric fibrin formation and lysis assay. Unit of measure: seconds. (in a subset of T2DM only, n=100 in total) |
| Fibrinolytic markers | Three months | Plasma concentrations of plasminogen activity, tissue plasminogen activator (unit of measure: ng/mL) and plasminogen activator inhibitor-1 (unit of measure: ng/mL) measured with ELISA (Technozym®, Technoclone, Vienna, Austria). (in a subset of T2DM only, n=100 in total) |
| Endothelial activation | Three months | Plasma concentrations of syndecan-1 (unit of measure: ng/mL) and thrombomodulin (unit of measure: ng/mL) measured with commercial ELISA kits (CD138 kit and CD141 kit, Diaclone, Medix Biochemica, Espoo, Finland). (in a subset of T2DM only, n=100 in total) |
| Inflammation | Three months | The effect of intervention on inflammatory markers (Olink panel) (in a subset of T2DM only, n=100 in total) |
| Oxidative stress | Three months | The effect of intervention on 8-Oxo-2'-deoxyguanosine levels (in a subset of T2DM only, n=100 in total) |
Countries
Denmark, Sweden
Contacts
STUDY_DIRECTOROle Frobert, Prof
Department of Cardiology, Örebro Univerity Hospital, 701 85 Örebro, Sweden
PRINCIPAL_INVESTIGATORCecilia Bergh, PhD
Clinical Epidemiology and Biostatistics, School of medical Sciences, örebro University, Sweden
Outcome results
None listed