Tight Glycemic Control Increases Cardiac Stem Cells During Acute Myocardial Infarction
Condition: Myocardial Infarction; Oxidative Stress; Glycemic Control
MeSH terms: Myocardial Infarction; Infarction
Study type: Interventional
Phase: Phase 4

Summary: 
      Objectives. The investigators analysed the effects of tight glycemic control in regenerative
      potential of the myocardium during acute myocardial infarction (AMI).

      Background. A strict glycemic control after AMI improves the cardiac outcome. The role of
      tight glycemic control in regenerative potential of the myocardium during acute myocardial
      ischemia are still largely unknown.

      Methods. Sixty-five patients with first AMI undergoing coronary bypass surgery were studied:
      25 normoglycemic patients served as control group; hyperglycemic patients (glucose >140
      mg/dl) were randomized to intensive glycemic control (IGC, n=20; glucose goal 80-140 mg/dl)
      or conventional glycemic control (CGC, n=20; glucose goal180-200 mg/dl) for almost 3 days
      before surgery, using insulin infusion followed by subcutaneous insulin treatment.
      Echocardiographic parameters were investigated at admission and after treatment period.
      During surgery, oxidative stress (nitrotyrosine, O2- production), apoptosis (Caspase-3) and
      cardiac stem cells (CSCs) (c-kit, MDR1 and Sca-1 positive cells) were analysed in biopsy
      specimens taken from the peri-infarcted area.
    

Detailed description: 
      The study design was structured on the basis of protocol Yale . Upon emergency wards
      admission, hyperglycemic patients were randomly assigned to IGC or CGC. In patients with
      STEMI the insulin infusion was started after thrombolysis. In the CGC group, continuous
      insulin infusion of 50 IU Actrapid HM (Novo Nordisk) in 50 ml NaCl (0.9% using a Perfusor-FM
      pump) was started only when blood glucose levels exceeded 200 mg/dl and adjusted to keep
      blood glucose between 180 and 200 mg/dl. When blood glucose fell <180 mg/dl, insulin infusion
      was slowed down and eventually stopped. In the IGC group, insulin infusion was started when
      blood glucose levels exceeded 140 mg/dl and adjusted to maintain glycemia at 80-140 mg/dl.
      During insulin infusion, oral feeding was stopped and parenteral nutrition (13±5
      Kcal/kg-1/day-1) was started. After the start of insulin infusion protocol a glycemic control
      was provided every hour in order to obtain three consecutive values that were within the goal
      range. Capillary glucose levels were measured by fingerstick testing. Additionally, plasma
      glucose levels were checked every two hours in both CGC and IGT patients throughout the study
      period. Both measurements were no statistically different . The infusion lasted until stable
      glycemic goal (ICG group: 80-140 mg/dl; CGC group: 180-200 mg/dl) at least for 24 h. After
      glycemic goal were maintained for 24 h, a parenteral nutrition was stopped and feeding was
      started according to European guidelines (10). Subcutaneous insulin was initiated at the
      cessation of the infusion. Insulin was given as short-acting insulin before meals and
      intermediate long-acting insulin in the evening, in both group. In IGC group, the treatment
      goal was a fasting blood glucose level of 90-140 mg/dl and a non-fasting (two hours after
      meal) level of <180 mg/dl (4). In CGC group, the treatment goal was fasting blood glucose and
      postprandial levels of <200 mg/dl. With regard to the full medical therapy, the protocol
      stated that the use of concomitant treatment should be as uniform as possible and according
      to evidence-based international guidelines for AMI.

      Echocardiographic assessment. Patients enrolled in the study underwent two-dimensional
      echocardiography at admission before starting full medical therapy as well as after achieved
      glycemic control goal for almost 3 days, before surgery. The study was performed using a
      standardized protocol and phased-array echocardiographs with M-mode, two-dimensional, and
      pulsed, continuous-wave, and color flow Doppler capabilities. The ejection fraction was
      calculated from area measurements using the area-length method applied to the average apical
      area. The left ventricular internal dimension and interventricular septal were measured at
      the end diastole and end systole, and the wall motion score index was calculated according to
      American Society of Echocardiography recommendations. Isovolumetric relaxation time (IRT) was
      the time interval from cessation of left ventricular outflow to onset of mitral inflow, the
      ejection time (ET) was the time interval between the onset and the cessation of left
      ventricular outflow, and the mitral early diastolic flow deceleration time was the time
      interval between the peak early diastolic flow velocity and the end of the early diastolic
      flow. The total systolic time interval was measured from the cessation of one mitral flow to
      the beginning of the following mitral inflow. Isovolumetric contracting time (ICT) was
      calculated by subtracting ET and IRT from the total systolic time interval. The ratio of
      velocity time intervals (vti) of mitral early (E) and late (A) diastolic flows (Evti/Avti)
      was calculated. The myocardial performance index (MPI) was calculated as (IRT+ICT)/ET.

      Biopsy of myocardium. All patients were undergone to CABG after maintained glucose goal for
      almost 3 days. After induction of anaesthesia and median sternotomy, the heart of each
      patient was examined, and 3-mm partial-thickness biopsy specimens were taken from the
      peri-infarcted area. The infarcted zone was identified as a yellow area surrounded by a
      purple band of granulation tissue or as gray area with fine yellow lines at its periphery.
      The peri-infarct zone was identified as a zone immediately adjacent the zone with the
      anatomical characteristics of myocardial infarct. Moreover, the transesophageal
      echocardiogram (TEE) was performer to evaluate peri-infarct zone All biopsies were performed
      before CABG, during ventilation with a fraction of inspired oxygen of 40% and peripheral
      oxygen saturations of >95%.

      Analysis of specimens. Half of each biopsy specimen was fixed in formalin, sectioned to a
      thickness of 5 µm, mounted on slides, and stained with hematoxylin and eosin. The mounted
      specimens were then examined for evidence of ischemia or kept for immunohistechemistry. The
      other half of the specimen was frozen in liquid nitrogen for Western Blotting analysis.
    

Intervention name(s): Insulin
Intervention type(s): Drug
Intervention description(s): In the CGC group, continuous insulin infusion was started only when blood glucose levels exceeded 200 mg/dl and adjusted to keep blood glucose between 180 and 200 mg/dl. When blood glucose fell <180 mg/dl, insulin infusion was tapered slowed down and eventually stopped. In the IGC group, insulin infusion was started when blood glucose levels exceeded 140 mg/dl and adjusted to maintain glycemia at 80-140 mg/dl. After the start of insulin infusion protocol a glycemic control was provided every hour in order to obtain three consecutive values that were within the goal range. Plasma glucose levels were checked every two hours in both CGC and IGT patients throughout the study period. The infusion lasted until stable glycemic goal (ICG group: 80-140 mg/dl; CGC group: 180-200 mg/dl) at least for 24 h. Subcutaneous insulin was initiated at the cessation of the infusion. Insulin was given as short-acting insulin before meals and intermediate long-acting insulin in the evening, in both group.
Intervention MeSH terms: Insulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: myocardial infarction; oxidative stress; stem cells; glycemic control