Regadenoson Blood Flow in Type 1 Diabetes (RABIT1D)
Condition: Coronary Artery Disease; Type 1 Diabetes Mellitus
MeSH terms: Coronary Artery Disease; Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 4

Summary: 
      Cardiovascular disease (CVD) remains the major cause of mortality and morbidity in both type
      1 (T1D) and type 2 (T2D) diabetes patients; modifications of traditional CVD risk factors
      have had a limited impact. This project called Regadenoson Blood flow in Type 1 Diabetes
      (RABIT1D) and is proposed as a sub-study of the Coronary Artery Calcification in Type 1
      Diabetes (CACTI) study, which has established a unique cohort of 656 T1D patients (age 20-55,
      minimal diabetes duration of 10 yrs) and 764 non-diabetic controls. This cohort is being
      followed for progression of coronary artery calcification (CAC) measured using the electron
      beam tomography (EBT) for development of clinical CVD. Participants have been well
      characterized during the baseline examination (4/00-3/02) and two follow-up re-examinations 3
      and 6 years later. The study has provided important insights into the risk factors and
      possible prevention of premature CVD in T1D. We are proposing assess a subset of this
      population to determine vasodilatory reserve as it relates to early coronary atherosclerosis
      in T1D.

      Hypothesis: that myocardial blood imaging (MBF) reserve can be measured in Type 1 diabetes
      mellitus (DM) using regadenoson stress cardiac magnetic resonance and that significantly
      reduced MBF is a marker of extensive atherosclerotic disease correlated to coronary arterial
      calcification, plaque formation and impaired vasodilatory reserve.
    

Detailed description: 
      The CACTI cohort is being followed for progression of coronary artery calcification (CAC) for
      development of clinical CVD and participants have been characterized during the baseline
      examination (4/00-3/02) and two follow-up re-examinations 3 and 6 years later. We are
      proposing assess a subset of this population to determine vasodilatory reserve as it relates
      to early coronary atherosclerosis in T1D. In the CACTI Study sought to determine the
      relationship between risk factors for CAD and coronary arterial calcification in T1D subjects
      compared to an age and gender matched control cohort. The trial identified CAC as a high risk
      marker of CAD and was more extensive in diabetic patients.

      T1D patients have more CAC than nondiabetic controls but they also appear to have more
      impaired coronary vasoreactive function. Impaired response to acetylcholine testing and
      adenosine vasodilation are reported in diabetic subjects. The relationship between coronary
      microvascular dysfunction and diabetic cardiomyopathy is supported by observation of similar
      microvascular abnormalities. Endothelial dysfunction not only precedes and predicts clinical
      macrovascular disease, but also is an independent prognostic marker of adverse long-term
      cardiovascular outcomes. Significantly greater CAC in T1D was also noted than in non-DM
      subjects. There is also a greater rate of increase noted in the CACTI cohort.

      Myocardial Flow Reserve by MRI: Myocardial perfusion distribution and myocardial blood flow
      reserve can be simultaneously assessed using a MRI first-pass Gd contrast injection approach.
      Rapid MR imaging (MRI) during the first pass injection of Gd compounds is used to assess
      myocardial perfusion with a spatial resolution of 2-3 mm, and to detect any regional
      impairments of myocardial blood flow (MBF) that may lead to ischemia. The myocardial
      perfusion reserve (MPR) is a useful concept for quantifying the vasodilator response. The
      perfusion reserve can be estimated from the ratio of MBFs during vasodilation and at
      baseline, similar to that described by labeled microspheres. Assessment of myocardial blood
      flow and flow reserve by cardiac MR is a robust technique. There is a relationship between
      CAC and hyperemic flow reserve, although it may be more or less strong depending upon the
      methodology employed. However, CAC is still a marker of the atherosclerotic process and this
      process appears to be more aggressive in T1D. The investigation of MBF reserve as a marker of
      early or more aggressive vasculopathy is important, especially in a disease with significant
      morbidity and mortality from cardiovascular events.

      Regadenoson Vasodilation: Regadenoson is a selective A2A adenosine receptor agonist FDA
      released as a pharmacologic vasodilator in nuclear stress myocardial perfusion imaging (MPI).
      It has a higher affinity for A2A receptors than adenosine and is a more potent coronary
      vasodilator. Adenosine infusion is the gold standard for both invasive and non-invasive
      assessment of myocardial blood flow reserve, yet regadenoson with potentially greater
      coronary arterial vasodilation and a simple bolus injection is an ideal agent with which to
      study differences in CFR between different disease states. Limited data is published on the
      utility of regadenoson in invasive assessment of CFR and no data are published regarding the
      utility of this agent in assessing the hyperemic myocardial blood flow response with respect
      to cardiac MRI.

      Research Design and Methods POPULATION CACTI Diabetes Study: We propose to recruit subjects
      from the CACTI cohort into this sub-study by focusing on individuals completing 6-yr
      follow-up.

      Imaging Studies Non-DM CAC>100 T1D CAC< 100 T1D CAC> 100 MPI 5 10 10 CMR 5 10 10 InvCBF 5
      5-10 5-10 Subject will be recruited to complete all three parts of the protocol myocardial
      perfusion imaging (MPI); cardiac MR assessment of myocardial blood flow reserve (MBF); and
      only those subject with significant symptoms or clinical indications proceeding to invasive
      "Catheterization Laboratory" assessment of CBF reserve (Invasive CBF) Aim 1. Determine the
      relationship between myocardial perfusion index, regional CBF and invasively measured
      coronary perfusion reserve The first approach will be to assess the differences in myocardial
      perfusion between T1D and non-DM subjects employing vasodilatory stress with regadenoson. The
      myocardial perfusion index as described previously will be calculated for each individual.
      The relative perfusion index will be directly compared to the invasively obtained CBF reserve
      in each vascular territory assessed.

      Stress Myocardial Perfusion Protocols. Subjects will undergo regadenoson stress MPI with 400
      mcg administered as a 10 second bolus followed by injection of 30 mCi of Tc-99m-sestamibi.
      Gated SPECT perfusion imaging is then performed within 30 minutes. A rest study is performed
      on a separate day with a similar sestamibi dose administered.

      Acquisition Protocol. All SPECT studies are performed with parallel hole collimators and
      gated acquisitions protocol (10% RR window) acquired into 16 time bins. Data Processing of
      Gated data sets are assessed for mean counts, corrected for dose, decay and time of imaging,
      are measured in each segment utilizing 4D-MSPECT (INVIA, Ann Arbor, Michigan). MPI is defined
      as the corrected stress counts divided by corrected rest counts.

      Statistical Analysis: Based upon our prior experience approximately a third of the T1D
      subjects will have a MP index of less that 1.5 to direct compare to the invasive measured
      flow reserve. This maybe treated as a binary variable or as a continuous variable by
      combining all T1D subject compared to the non-DM control subjects. Data will be analyzed
      using unpaired t-test, linear and logistic regression. Continuous variables are expressed as
      mean ± standard deviation (SD) and are compared across groups by use of unpaired t-tests. All
      statistical analysis will be performed using two-sided tests with p < 0.05 considered
      statistically significant.

      Aim 2. Measure coronary blood flow using Regadenoson stress CMR to determine the MBF reserve
      in type 1 DM subjects compared to non-diabetic controls. Using the method of a two
      compartment model with K trans function analysis, we will determine the myocardial blood flow
      reserve by cardiac MR. This approach will use regadenoson bolus as the vasodilator for the
      hyperemic response of the coronary arterial bed. We will assess the relationship of MBF
      reserve or lack of reserve to disease state i.e T1D to non-DM subjects. In addition we will
      regionally compare MBF reserve to the MP index obtained from radionuclide techniques by
      coronary vascular territories. Similarly CAC values obtained at the 6-yr CACTI follow-up
      study will be directly compared to blood flow measurement within coronary vascular
      distributions.

      CMR Protocol: An IV injection into the antecubital vein and connected to a power injector
      will be performed in the MR scanner for functional and perfusion imaging (Symphony 1.5 T,
      Siemens Medical). All images are acquired with a 4 channel phased array surface coil. Blood
      flow imaging is performed in three short-axis simultaneous slices (basal, mid and apical)
      acquired during an initial bolus injection of gadolinium (0.04 mmol/kg at a rate of 5 ml/sec)
      followed by a 10-ml saline flush administered using the power injector. ProHance is used due
      to its lower viscosity as the contrast agent. The short-axis slices are acquired using a SSFP
      imaging sequence with, TR/TE/flip 185ms/1.2ms/50 degrees dynamically acquired and inserted
      into a 330x 380 matrix). Images are acquired using a field of view ranging from 280 to 400
      mm. A first perfusion scan will be performed at rest, followed by a second scan during
      maximal vasodilation about 15 min later. Hyperemia will be initiated with administration of
      400 mcg bolus injection of regadenoson and acquisition started 1 minute post regadenoson
      administration. Subjects will be monitored using MRI compatible blood pressure monitoring and
      single lead ECG monitoring.

      Data analysis Quantitative analysis of the MR blood flow data will be performed on a Leonardo
      Workstation using Argus perfusion analysis software. Images were registered manually by
      adjusting the horizontal and vertical registration of each frame. The left and right
      ventricular blood pool and six myocardial regions will be analyzed to extract the linear
      slope during the initial signal increase as well as the starting and peak signal intensities.
      To extract the slope, base, and peak signals, a line was manually fitted to the upslope
      signal (typically 4-6 time points), and the base and peak positions of the upslope data were
      manually identified. Normalized slope (SlopeN) was calculated by division by the left
      ventricular blood pool slope, and the net signal gain (SG) determined by subtracting the
      initial from the peak signal intensity. The myocardial flow reserve index was calculated for
      each myocardial region as the ratio of the normalized hyperemic time-intensity slope to the
      normalized baseline time-intensity slope.

      Statistical Analysis: Based upon prior experience in the literature approximately a third of
      the T1D subjects will have a MP index of less than 1.5 to direct compare to the invasive
      measured flow reserve. Data will be analyzed using unpaired t-test, linear and logistic
      regression.

      Aim 3. Determine the relationship between CBF reserve in vascular distributions to the degree
      of coronary arterial calcification.

      Coronary artery calcification. All returning patients have previously undergone EBT scan.
      These data as described above will be used to compare to the new MPI, CMR myocardial blood
      flow reserve, and to the invasively measured CFR. Regional change will determined within
      standard coronary vascular distributions.

      Flow Reserve Substudy Protocol: High-risk diabetics with CAC> 100 (n=10) and stratified
      random sample high risk non-diabetics (n=10) will be studied. The inclusion of subjects with
      an abnormal perfusion reserve is important, because this value identified subjects with high
      risk in the first phase of the study and therefore is used to select individuals with high
      risk of cardiac events that clinically would undergo invasive assessment of coronary anatomy.
      Perfusion imaging will then be the test that stratifies subjects into an additional higher
      risk than the CAC > 100. Selected patients identified as part of Specific Aim 2 will undergo
      a clinically indicated cardiac catheterization and baseline CFR study. Coronary angiography
      is the clinically accepted standard for evaluation and diagnosis of coronary artery disease.

      Subsequently, coronary artery vasodilator reserve will be assessed using the regadenoson
      intravenous challenge technique measured as the coronary flow reserve and fraction flow
      reserve assess by a Doppler flow guide wire.

      Methods for Flow Reserve:Selective coronary angiography is performed using standard technique
      with 5F diagnostic catheters in the LCA and RCA. The artery or interest determined by the
      abnormal area of myocardial perfusion by SPECT or MR imaging will be interrogated. The artery
      of interest will be cannulated with a 6F or 7F Guide catheter. A 0.014 in x 300cm pressure
      and Doppler-tipped guidewire (CombMap XT, Volcano Corp) will be advanced into the distal bed
      of the vessel of interest. After optimization of the pressure and Doppler signal, velocity
      and pressure measurements will be obtained at rest and after induction of maximal hyperemia
      with an intravenous bolus of regadenoson. Coronary flow reserve (CFR) will be measured in the
      target vessel of interest after 1-2 minutes following the IV bolus. Absolute CFVR will be
      calculated as the ratio of hyperemic to baseline average peak flow velocity and the relative
      CFVR as the ratio of the absolute CFVR in the target vessel to the absolute CFVR in the
      reference artery. FFR and CFR values will be categorized according to published cut-off
      values of 0.75 and 2.0, respectively.
    

Intervention name(s): Regadenoson myocardial perfusion imaging; Regadenoson MRI myocardial blood flow
Intervention type(s): Drug; Drug
Intervention description(s): Myocardial perfusion imaging at rest and following 400mcg Regadenoson IV bolus pharmacologic stress with 30 mCi of Tc-99m sestamibi injected at both but the studies performed 48 hours apart.; CMR assessment of stress myocardial perfusion and blood flow after 400 mcg Regadenoson pharmacologic using gadolinium contrast (gadoteridol) 0.05mmole/kg at stress and rest.
Other intervention name(s): Cardiolite (sestamibi); Regadenoson (Lexiscan); Regadenoson (Lexiscan); Prohance (Gadoteridol)
Intervention MeSH terms: Regadenoson; Technetium Tc 99m Sestamibi
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Myocardial blood flow; Cardiac magnetic resonance imaging; Myocardial perfusion imaging; Coronary artery flow reserve; Regadenoson