Regadenoson Blood Flow in Type 1 Diabetes (RABIT1D)
Regadenoson Blood Flow in Type 1 Diabetes (RABIT1D)
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.
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.
Inclusion Criteria:

 -  1. Inclusion Criteria Nondiabetic controls High-risk (n=5)

 1. Completed visit 6yr f/u CACTI Trial

 2. No history of previous MI, revascularization or angina

 3. CAC > 100

 4. Stratified random sample to reflect age-sex- distribution of the high risk
 diabetic group T1Diabetic subjects High-risk group (n= 10)

 1. Completed visit 6yr f/u CACTI Trial

 2. No history of previous MI, revascularization or angina

 3. CAC > 100

 4. preferably MPR of > 1.5 T1Diabetic subjects Lower-risk group (n= 10)

 1. Completed visit 1.A and 1.B CACTI Trial

 2. No history of previous MI, revascularization or angina

 3. CAC < 100

 Exclusion Criteria:

 2. Exclusion Criteria:

 1. Pregnant or lactating women, women who plan to become pregnant

 2. Claustrophobia

 3. Moderate or severe congestive heart failure at baseline, Left ventricular
 ejection fraction (LVEF) < 25%

 4. Uncontrolled hypertension

 5. Unwillingness to complete all components of the study

 6. Significant CAD or prior revascularization

 7. Smoker

 8. Subject cannot have >50% reduction in lumen diameter of left main coronary artery

 9. Asthma requiring daily bronchodilators

 10. Methylxanthine therapy

 11. Moderate to severe renal insufficiency: GFR < 40 mL/min